TYK2 inhibitors and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. Ser. No.16/697,371, filed on Nov. 27, 2019, now issued as U.S. Pat. No.11,053,241, which claims the benefit of priority to U.S. provisionalpatent application Ser. No. 62/773,620, filed Nov. 30, 2018, theentirety of which is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful forinhibiting non-receptor tyrosine-protein kinase 2 (“TYK2”), also knownas Tyrosine kinase 2. The invention also provides pharmaceuticallyacceptable compositions comprising compounds of the present inventionand methods of using said compositions in the treatment of variousdisorders.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is the protein kinasefamily.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. Protein kinases are thought tohave evolved from a common ancestral gene due to the conservation oftheir structure and catalytic function. Almost all kinases contain asimilar 250-300 amino acid catalytic domain. The kinases may becategorized into families by the substrates they phosphorylate (e.g.,protein-tyrosine, protein-serine/threonine, lipids, etc.).

In general, protein kinases mediate intracellular signaling by effectinga phosphoryl transfer from a nucleoside triphosphate to a proteinacceptor that is involved in a signaling pathway. These phosphorylationevents act as molecular on/off switches that can modulate or regulatethe target protein biological function. These phosphorylation events areultimately triggered in response to a variety of extracellular and otherstimuli. Examples of such stimuli include environmental and chemicalstress signals (e.g., osmotic shock, heat shock, ultraviolet radiation,bacterial endotoxins, and H₂O₂), cytokines (e.g., interleukin-1 (IL-1),interleukin-8 (IL-8), and tumor necrosis factor α (TNF-α)), and growthfactors (e.g., granulocyte macrophage-colony-stimulating factor(GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulusmay affect one or more cellular responses related to cell growth,migration, differentiation, secretion of hormones, activation oftranscription factors, muscle contraction, glucose metabolism, controlof protein synthesis, and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggeredby kinase-mediated events. These diseases include, but are not limitedto, autoimmune diseases, inflammatory diseases, bone diseases, metabolicdiseases, neurological and neurodegenerative diseases, cancer,cardiovascular diseases, allergies and asthma, Alzheimer's disease, andhormone-related diseases. Accordingly, there remains a need to findprotein kinase inhibitors useful as therapeutic agents.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of TYK2 kinase.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with regulation of signalingpathways implicating TYK2 kinases. Such diseases, disorders, orconditions include those described herein.

Compounds provided by this invention are also useful for the study ofTYK2 enzymes in biological and pathological phenomena; the study ofintracellular signal transduction pathways occurring in bodily tissues;and the comparative evaluation of new TYK2 inhibitors or otherregulators of kinases, signaling pathways, and cytokine levels in vitroor in vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are usefulas inhibitors of TYK2 protein kinase.

The pseudokinase binding pocket of TYK2 contains a plurality ofhydration sites, each of which is occupied by a single molecule ofwater. Each of these water molecules has a stability rating associatedwith it. As used herein, the term “stability rating” refers to anumerical calculation which incorporates the enthalpy, entropy, and freeenergy values associated with each water molecule. This stability ratingallows for a measurable determination of the relative stability of watermolecules that occupy hydration sites in the binding pocket of TYK2.

Water molecules occupying hydration sites in the binding pocket of TYK2having a stability rating of >2.5 kcal/mol are referred to as “unstablewaters.”

Without wishing to be bound by any particular theory, it is believedthat displacement or disruption of an unstable water molecule (i.e., awater molecule having a stability rating of >2.5 kcal/mol), orreplacement of a stable water (i.e., a water molecule having a stabilityrating of <1 kcal/mol), by an inhibitor results in tighter binding ofthat inhibitor. Accordingly, inhibitors designed to displace one or moreunstable water molecules (i.e., those unstable water molecules notdisplaced by any known inhibitor) will be a tighter binder and,therefore, more potent inhibitor as compared to an inhibitor that doesnot displace unstable water molecules.

It was surprisingly found that provided compounds displace or disruptone or more unstable water molecules. In some embodiments, a providedcompound displaces or disrupts at least two unstable water molecules.

In certain embodiments, the present invention provides a compound offormula I.

or a pharmaceutically acceptable salt thereof, wherein each of X, L¹,R¹, R², and R³ is as defined below and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a pharmaceuticalcomposition comprising a compound of formula I, and a pharmaceuticallyacceptable carrier, adjuvant, or diluent.

In some embodiments, the present invention provides a method of treatinga TYK2-mediated disease, disorder, or condition comprising administeringto a patient in need thereof, a a compound of formula I or apharmaceutically acceptable salt thereof.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where unless otherwise specified, the radical orpoint of attachment is on the heteroaromatic ring or on one of the ringsto which the heteroaromatic ring is fused. Nonlimiting examples includeindolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl groupmay be mono- or bicyclic. The term “heteroaryl” may be usedinterchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or“heteroaromatic,” any of which terms include rings that are optionallysubstituted. The term “heteroaralkyl” refers to an alkyl groupsubstituted by a heteroaryl, wherein the alkyl and heteroaryl portionsindependently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms“heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—N(R^(∘))C(NR^(∘))N(R^(∘))₂; —(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘);—(CH₂)₀₋₄C(O)OR^(∘); —(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃;—(CH₂)₀₋₄OC(O)R^(∘); —OC(O)(CH₂)₀₋₄SR^(∘); —SC(S)SR^(∘);—(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘);—SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘);—C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; —SiR^(∘) ₃; —(C₁₋₄straight or branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight orbranched alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR^(•) ₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R, —S(O)₂NR^(†) ₂, —C(S)NR^(†)₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R; wherein each R^(†) isindependently hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R,taken together with their intervening atom(s) form an unsubstituted3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a warhead moiety, R¹, of a provided compound comprises oneor more deuterium atoms. In certain embodiments, Ring B of a providedcompound may be substituted with one or more deuterium atoms.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits TYK2 with measurable affinity. In certainembodiments, an inhibitor has an IC₅₀ and/or binding constant of lessthan about 50 μM, less than about 1 μM, less than about 500 nM, lessthan about 100 nM, less than about 10 nM, or less than about 1 nM.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in a TYK2 protein kinase activitybetween a sample comprising a compound of the present invention, orcomposition thereof, and a TYK2 protein kinase, and an equivalent samplecomprising an TYK2 protein kinase, in the absence of said compound, orcomposition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is N or CH;    -   L¹ is a covalent bond or a C₁₋₄ bivalent saturated or        unsaturated, straight or branched hydrocarbon chain wherein one        or two methylene units of the chain are optionally and        independently replaced by —C(R⁴)₂—, —N(R)—, —N(R)C(O)—,        —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—,        —C(O)O—, —S—, —S(O)— or —S(O)₂—;    -   R⁴ is independently R^(A) or R^(B);    -   each instance of R^(A) is independently halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)(NR)R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂,        —N(R)S(O)₂NR₂, —N(R)S(O)₂R, or —P(O)R₂; or two instances of        R^(A) are optionally taken together to form an oxo;    -   each instance of R^(B) is independently C₁₋₆ aliphatic; phenyl;        a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; an        8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; a 3-7        membered saturated or partially unsaturated monocyclic        carbocyclic ring; a 3-7 membered saturated or partially        unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; or a        7-12 membered saturated or partially unsaturated bicyclic        heterocyclic ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, and sulfur; each of which is substituted        by q instances of R^(C);    -   each instance of R^(C) is independently oxo, halogen, —CN, —NO₂,        —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)NR₂,        —N(R)S(O)₂NR₂, —N(R)S(O)₂R, —N═S(O)R₂, —S(NR)(O)R, —N(R)S(O)R,        —N(R)CN, —P(O)(R)NR₂, —P(O)(R)OR or —P(O)R₂ or an optionally        substituted group selected from C₁₋₆ aliphatic; phenyl;        naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having        1-5 heteroatoms independently selected from nitrogen, oxygen,        and sulfur; a 5-8 membered saturated or partially unsaturated        bridged bicyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, and sulfur; a 6-10 membered        saturated or partially unsaturated spirocyclic ring having 0-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; a 6-11 membered saturated or partially unsaturated        bicyclic heterocyclic ring having 1-2 heteroatoms independently        selected from nitrogen, oxygen, and sulfur; a 3-7 membered        saturated or partially unsaturated monocyclic heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, phosphorous, silicon and sulfur; and a 5-6 membered        monocyclic heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, and sulfur; or for each instance        of R^(B), optionally:        -   two R^(C) groups on the same atom are taken together with            the atom to form an optionally substituted 4-7 membered            saturated, spirocyclic heterocyclic ring having 1-2            heteroatoms, independently selected from nitrogen, oxygen,            and sulfur;        -   two R^(C) groups are taken together with their intervening            atoms to form an optionally substituted 4-7 membered            saturated or partially unsaturated, fused ring having 0-2            heteroatoms, independently selected from nitrogen, oxygen,            and sulfur; or        -   two R^(C) groups are taken together with their intervening            atoms to form an optionally substituted 5-6 membered fused            aryl ring having 0-3 heteroatoms, independently selected            from nitrogen, oxygen, and sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic; phenyl; naphthalenyl; an        8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; a 3-7        membered saturated or partially unsaturated monocyclic        heterocyclic ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or        partially unsaturated bicyclic heterocyclic ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; or:        -   two R groups on the same nitrogen are taken together with            the nitrogen to form an optionally substituted 4-7 membered            monocyclic saturated, partially unsaturated, or heteroaryl            ring having, in addition to the nitrogen, 0-3 heteroatoms            independently selected from nitrogen, oxygen, and sulfur;    -   R¹ is Cy¹;    -   Cy¹ is phenyl; a 5-6 membered monocyclic heteroaryl ring having        1-4 heteroatoms independently selected from nitrogen, oxygen,        and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; a 3-7 membered saturated or partially unsaturated        monocyclic heterocyclic ring having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; a 3-7        membered saturated or partially unsaturated monocyclic        carbocyclic ring; or a 7-12 membered saturated or partially        unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;        wherein Cy¹ is substituted with p instances of R^(1A);    -   each instance of R^(1A), is independently R^(A) or R^(B);    -   R² is C₁₋₆ aliphatic; phenyl; a 5-6 membered monocyclic        heteroaryl ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic        heteroaryl ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or        partially unsaturated monocyclic carbocyclic ring; a 3-7        membered saturated or partially unsaturated monocyclic        heterocyclic ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated        or partially unsaturated bicyclic heterocyclic ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; each of which is substituted by q instances of R^(C);    -   R³ is —C(O)NH₂, —C(O)NHCH₃, or —C(O)NHCD₃; and    -   each of p and q is independently 0, 1, 2, 3, or 4.

As described above, in certain embodiments, the present inventionprovides a compound of formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is N or CH;    -   L¹ is a covalent bond or a C₁₋₄ bivalent saturated or        unsaturated, straight or branched hydrocarbon chain wherein one        or two methylene units of the chain are optionally and        independently replaced by —C(R⁴)₂—, —N(R)—, —N(R)C(O)—,        —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—,        —C(O)O—, —S—, —S(O)— or —S(O)₂—;    -   R⁴ is independently R^(A) or R^(B);    -   each instance of R^(A) is independently halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)(NR)R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂,        —N(R)S(O)₂NR₂, —N(R)S(O)₂R, or —P(O)R₂; or two instances of        R^(A) are optionally taken together to form an oxo;    -   each instance of R^(B) is independently C₁₋₆ aliphatic; phenyl;        a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; an        8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; a 3-7        membered saturated or partially unsaturated monocyclic        carbocyclic ring; a 3-7 membered saturated or partially        unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; or a        7-12 membered saturated or partially unsaturated bicyclic        heterocyclic ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, and sulfur; each of which is substituted        by q instances of R^(C);    -   each instance of R^(C) is independently oxo, halogen, —CN, —NO₂,        —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)NR₂,        —N(R)S(O)₂NR₂, —N(R)S(O)₂R, —N═S(O)R₂, —S(NR)(O)R, —N(R)S(O)R,        —N(R)CN, —P(O)(R)NR₂, —P(O)(R)OR or —P(O)R₂ or an optionally        substituted group selected from C₁₋₆ aliphatic; phenyl;        naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having        1-5 heteroatoms independently selected from nitrogen, oxygen,        and sulfur; a 5-8 membered saturated or partially unsaturated        bridged bicyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, and sulfur; a 6-10 membered        saturated or partially unsaturated spirocyclic ring having 0-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; a 6-11 membered saturated or partially unsaturated        bicyclic heterocyclic ring having 1-2 heteroatoms independently        selected from nitrogen, oxygen, and sulfur; a 3-7 membered        saturated or partially unsaturated monocyclic heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, phosphorous, silicon and sulfur; and a 5-6 membered        monocyclic heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, and sulfur; or for each instance        of R^(B), optionally:        -   two R^(C) groups on the same atom are taken together with            the atom to form an optionally substituted 4-7 membered            saturated, spirocyclic heterocyclic ring having 1-2            heteroatoms, independently selected from nitrogen, oxygen,            and sulfur;        -   two R^(C) groups are taken together with their intervening            atoms to form an optionally substituted 4-7 membered            saturated or partially unsaturated, fused ring having 0-2            heteroatoms, independently selected from nitrogen, oxygen,            and sulfur; or        -   two R^(C) groups are taken together with their intervening            atoms to form an optionally substituted 5-6 membered fused            aryl ring having 0-3 heteroatoms, independently selected            from nitrogen, oxygen, and sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic; phenyl; naphthalenyl; an        8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; a 3-7        membered saturated or partially unsaturated monocyclic        heterocyclic ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or        partially unsaturated bicyclic heterocyclic ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; or:        -   two R groups on the same nitrogen are taken together with            the nitrogen to form an optionally substituted 4-7 membered            monocyclic saturated, partially unsaturated, or heteroaryl            ring having, in addition to the nitrogen, 0-3 heteroatoms            independently selected from nitrogen, oxygen, and sulfur;    -   R¹ is Cy¹;    -   Cy¹ is phenyl; a 5-6 membered monocyclic heteroaryl ring having        1-4 heteroatoms independently selected from nitrogen, oxygen,        and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; a 3-7 membered saturated or partially unsaturated        monocyclic heterocyclic ring having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur; a 3-7        membered saturated or partially unsaturated monocyclic        carbocyclic ring; or a 7-12 membered saturated or partially        unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;        wherein Cy¹ is substituted with p instances of R^(1A);    -   each instance of R^(1A), is independently R^(A) or R^(B);    -   R² is C₁₋₆ aliphatic; phenyl; a 5-6 membered monocyclic        heteroaryl ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic        heteroaryl ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or        partially unsaturated monocyclic carbocyclic ring; a 3-7        membered saturated or partially unsaturated monocyclic        heterocyclic ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated        or partially unsaturated bicyclic heterocyclic ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; each of which is substituted by q instances of R^(C);    -   R³ is —C(O)NH₂, —C(O)NHCH₃, or —C(O)NHCD₃;    -   each of p and q is independently 0, 1, 2, 3, or 4; and    -   r is 0 or 1.

As defined generally above, X is N or CH. In some embodiments, X is N.In some embodiments, X is CH.

In some embodiments, X is selected from those depicted in Table 1,below.

As defined generally above, L¹ is a covalent bond or a C₁₋₄ bivalentsaturated or unsaturated, straight or branched hydrocarbon chain whereinone or two methylene units of the chain are optionally and independentlyreplaced by —C(R⁴)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—,—S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O)₂—.

In some embodiments, L¹ is a covalent bond.

In some embodiments, L¹ is a C₁₋₄ bivalent saturated or unsaturated,straight or branched hydrocarbon chain wherein one or two methyleneunits of the chain are optionally and independently replaced by—C(R⁴)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—,—C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O)₂—.

In some embodiments, L¹ is a C₁₋₄ bivalent saturated, straight orbranched hydrocarbon chain wherein one or two methylene units of thechain are optionally and independently replaced by —C(R⁴)₂—, —N(R)—,—N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—,—C(O)O—, —S—, —S(O)—, or —S(O)₂—. In some embodiments, L¹ is a C₁₋₄bivalent unsaturated, straight or branched hydrocarbon chain wherein oneor two methylene units of the chain are optionally and independentlyreplaced by —C(R⁴)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—,—S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O)₂—.

In some embodiments, L¹ is a C₁₋₄ bivalent saturated, straight orbranched hydrocarbon chain wherein one methylene unit of the chain isoptionally replaced by —C(R⁴)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—,—N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or—S(O)₂—. In some embodiments, L¹ is a C₁₋₄ bivalent unsaturated,straight or branched hydrocarbon chain wherein one methylene unit of thechain is optionally replaced by —C(R⁴)₂—, —N(R)—, —N(R)C(O)—,—C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—,—S—, —S(O)—, or —S(O)₂—.

In some embodiments, L¹ is a C₁₋₄ bivalent saturated or unsaturated,straight or branched hydrocarbon chain. In some embodiments, L¹ is aC₁₋₄ bivalent saturated, straight or branched hydrocarbon chain. In someembodiments, L¹ is a C₁₋₄ bivalent unsaturated, straight or branchedhydrocarbon chain.

In some embodiments, L¹ is a covalent bond, —C(R⁴)₂—, —N(R)—, or —O—. Insome embodiments, L¹ is a covalent bond or —N(R)—. In some embodiments,L¹ is —C(R⁴)₂—, —N(R)—, or —O—. In some embodiments, L¹ is a covalentbond, —C(H)₂—, —N(H)—, or —O—. In some embodiments, L¹ is a covalentbond or —N(H)—. In some embodiments, L¹ is —C(H)₂—, —N(H)—, or —O—.

In some embodiments, L¹ is selected from those depicted in Table 1,below.

As defined generally above, each instance of R⁴ is independently R^(A)or R^(B). In some embodiments, R⁴ is R^(A). In some embodiments, R⁴ isR^(B).

In some embodiments, R⁴ is halogen; —OR; C₁₋₆ aliphatic, optionallysubstituted by q instances of R^(C); or two instances of R⁴ are takentogether to form an oxo. In some embodiments, two instances of R⁴ aretaken together to form an oxo. In some embodiments, R⁴ is halogen. Insome embodiments, R⁴ is —OR. In some embodiments, R⁴ is C₁₋₆ aliphatic,optionally substituted by q instances of R^(C). In some embodiments, R⁴is C₁₋₃ aliphatic.

In some embodiments, R⁴ is selected from those depicted in Table 1,below.

As defined generally above, each instance of R^(A) is independentlyhalogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)(NR)R, —S(O)₂NR₂,—S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R,—OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂,—N(R)S(O)₂NR₂, —N(R)S(O)₂R, or —P(O)R₂, or two instances of R^(A) areoptionally taken together to form an oxo.

In some embodiments, each instance of R^(A) is independently halogen,—CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)(NR)R, —S(O)₂NR₂, —S(O)R,—S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,—N(R)C(O)OR, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, or—P(O)R₂. In some embodiments, two instances of R^(A) are taken togetherto form an oxo.

In some embodiments, R^(A) is halogen. In some embodiments, R^(A) is—CN. In some embodiments, R^(A) is —NO₂. In some embodiments, R^(A) is—OR. In some embodiments, R^(A) is —SR. In some embodiments, R^(A) is—NR₂. In some embodiments, R^(A) is —S(O)₂R. In some embodiments, R^(A)is —S(O)(NR)R. In some embodiments, R^(A) is —S(O)₂NR₂. In someembodiments, R^(A) is —S(O)R. In some embodiments, R^(A) is —S(O)NR₂. Insome embodiments, R^(A) is —C(O)R. In some embodiments, R^(A) is—C(O)OR. In some embodiments, R^(A) is —C(O)NR₂. In some embodiments,R^(A) is —C(O)N(R)OR. In some embodiments, R^(A) is —OC(O)R. In someembodiments, R^(A) is —OC(O)NR₂. In some embodiments, R^(A) is—N(R)C(O)OR. In some embodiments, R^(A) is —N(R)C(O)NR₂. In someembodiments, R^(A) is —N(R)C(NR)NR₂. In some embodiments, R^(A) is—N(R)S(O)₂NR₂. In some embodiments, R^(A) is —N(R)S(O)₂R. In someembodiments, R^(A) is —P(O)R₂.

In some embodiments, R^(A) is halogen, —CN, or —NO₂. In someembodiments, R^(A) is —OR, —SR, or —NR₂. In some embodiments, R^(A) is—S(O)₂R, —S(O)(NR)R, —S(O)₂NR₂, —S(O)R, or —S(O)NR₂. In someembodiments, R^(A) is —C(O)R, —C(O)OR, —C(O)NR₂, or —C(O)N(R)OR. In someembodiments, R^(A) is —OC(O)R or —OC(O)NR₂. In some embodiments, R^(A)is —N(R)C(O)OR, —N(R)C(O)NR₂, or —N(R)C(NR)NR₂. In some embodiments,R^(A) is —N(R)S(O)₂NR₂ or —N(R)S(O)₂R.

In some embodiments, R^(A) is —S(O)₂R, —S(O)₂NR₂, —S(O)R, or —S(O)NR₂.In some embodiments, R^(A) is —N(R)C(O)OR or —N(R)C(O)NR₂.

In some embodiments, R^(A) is halogen, —CN, —OR, —SR, —NR₂, —OC(O)R,—OC(O)NR₂, or two instances of R^(A) are taken together to form an oxo.In some embodiments, R^(A) is halogen, —OR, or two instances of R^(A)are taken together to form an oxo.

In some embodiments, R^(A) is halogen, —CN, —OR, —SR, —NR₂, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, or two instances of R^(A) are takentogether to form an oxo. In some embodiments, R^(A) is halogen, —CN,—OR, —NR₂, —C(O)NR₂, or two instances of R^(A) are taken together toform an oxo.

In some embodiments, R^(A) is selected from those depicted in Table 1,below.

As defined generally above, each instance of R^(B) is independently C₁₋₆aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; an8-10 membered bicyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 3-7 memberedsaturated or partially unsaturated monocyclic carbocyclic ring; a 3-7membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur; or a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; each of which is substituted by qinstances of R^(C).

In some embodiments, R^(B) is C₁₋₆ aliphatic, substituted by q instancesof R^(C). In some embodiments, R^(B) is C₁₋₆ aliphatic. In someembodiments, R^(B) is C₁₋₃ aliphatic, optionally substituted by qinstances of R^(C). In some embodiments, R^(B) is C₁₋₃ aliphatic.

In some embodiments, R^(B) is phenyl; a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; a 3-7 membered saturated or partially unsaturated monocycliccarbocyclic ring; a 3-7 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturatedor partially unsaturated bicyclic heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of which is substituted by q instances of R^(C).

In some embodiments, R^(B) is phenyl, substituted with q instances ofR^(C). In some embodiments, R^(B) is a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; substituted with q instances of R^(C). Insome embodiments, R^(B) is an 8-10 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; substituted with q instances of R^(C). In some embodiments,R^(B) is a 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; substituted with q instances of R^(C). Insome embodiments, R^(B) is a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring; substituted with q instances ofR^(C). In some embodiments, R^(B) is a 7-12 membered saturated orpartially unsaturated bicyclic heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; substitutedwith q instances of R^(C).

In some embodiments, R^(B) is phenyl or a 3-7 membered saturated orpartially unsaturated monocyclic carbocyclic ring; each of which issubstituted with q instances of R^(C). In some embodiments, R^(B) is a5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; an 8-10membered bicyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora 7-12 membered saturated or partially unsaturated bicyclic heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each of which is substituted with q instances ofR^(C). In some embodiments, R^(B) is a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; or an 8-10 membered bicyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each of which is substituted with q instances ofR^(C). In some embodiments, R^(B) is a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora 7-12 membered saturated or partially unsaturated bicyclic heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each of which is substituted with q instances ofR^(C).

In some embodiments, R^(B) is phenyl; a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 3-7 memberedsaturated or partially unsaturated monocyclic carbocyclic ring; each ofwhich is substituted with q instances of R^(C). In some embodiments,R^(B) is an 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora 7-12 membered saturated or partially unsaturated bicyclic heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each of which is substituted with q instances ofR^(C).

In some embodiments, R^(B) is a 3-7 membered saturated monocycliccarbocyclic ring, substituted by q instances of R^(C). In someembodiments, R^(B) is a 3-7 membered partially unsaturated monocycliccarbocyclic ring, substituted by q instances of R^(C). In someembodiments, R^(B) is a 3-7 membered saturated or partially unsaturatedmonocyclic carbocyclic ring. In some embodiments, R^(B) is cyclopropyl.

In some embodiments, R^(B) is C₁₋₆ aliphatic; phenyl; a 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring; or a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of which is substituted with q instances of R^(C).

In some embodiments, R^(B) is C₁₋₆ aliphatic; phenyl; or a 3-7 memberedsaturated or partially unsaturated monocyclic carbocyclic ring; each ofwhich is substituted with q instances of R^(C). In some embodiments,R^(B) is a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; each of which is substituted with qinstances of R^(C).

In some embodiments, R^(B) is a 5-6 membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; a 3-7 membered saturated or partially unsaturated monocycliccarbocyclic ring; or a 3-7 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; each of which is substitutedwith q instances of R^(C).

In some embodiments, R^(B) is selected from those depicted in Table 1,below.

As defined generally above, R^(C) is independently oxo, halogen, —CN,—NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)NR₂, —N(R)S(O)₂NR₂,—N(R)S(O)₂R, —N═S(O)R₂, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR₂,—P(O)(R)OR or —P(O)R₂ or an optionally substituted group selected fromC₁₋₆ aliphatic; phenyl; naphthalenyl; an 8-10 membered bicyclicheteroaryl ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 5-8 membered saturated or partiallyunsaturated bridged bicyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated orpartially unsaturated spirocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 6-11membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur; a 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, phosphorous, silicon and sulfur; and a 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; or for each instance of R^(B),optionally:

-   -   two R^(C) groups on the same atom are taken together with the        atom to form an optionally substituted 4-7 membered saturated,        spirocyclic heterocyclic ring having 1-2 heteroatoms,        independently selected from nitrogen, oxygen, and sulfur;    -   two R^(C) groups are taken together with their intervening atoms        to form an optionally substituted 4-7 membered saturated or        partially unsaturated, fused ring having 0-2 heteroatoms,        independently selected from nitrogen, oxygen, and sulfur; or    -   two R^(C) groups are taken together with their intervening atoms        to form an optionally substituted 5-6 membered fused aryl ring        having 0-3 heteroatoms, independently selected from nitrogen,        oxygen, and sulfur.

In some embodiments, R^(C) is oxo, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)C(NR)NR₂, —N(R)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, —N═S(O)R₂,—S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR₂, —P(O)(R)OR or —P(O)R₂ oran optionally substituted group selected from C₁₋₆ aliphatic; phenyl;naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur; a5-8 membered saturated or partially unsaturated bridged bicyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; a 6-10 membered saturated or partially unsaturated spirocyclicring having 0-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur; a 6-11 membered saturated or partially unsaturatedbicyclic heterocyclic ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, phosphorous, silicon andsulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, two R^(C) groups on the same atom are takentogether with the atom to form an optionally substituted 4-7 memberedsaturated, spirocyclic heterocyclic ring having 1-2 heteroatoms,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, two R^(C) groups are taken together with theirintervening atoms to form an optionally substituted 4-7 memberedsaturated or partially unsaturated, fused ring having 0-2 heteroatoms,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, two R^(C) groups are taken together with theirintervening atoms to form an optionally substituted 5-6 membered fusedaryl ring having 0-3 heteroatoms, independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R^(C) is oxo, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)C(NR)NR₂, —N(R)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, —N═S(O)R₂,—S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR₂, —P(O)(R)OR or —P(O)R₂ oran optionally substituted C₁₋₆ aliphatic. In some embodiments, R^(C) isan optionally substituted group selected from phenyl; naphthalenyl; an8-10 membered bicyclic heteroaryl ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 5-8 memberedsaturated or partially unsaturated bridged bicyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, and sulfur; a6-10 membered saturated or partially unsaturated spirocyclic ring having0-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur; a 6-11 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, phosphorous, silicon andsulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(C) is oxo, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, or —N(R)S(O)R, or anoptionally substituted C₁₋₆ aliphatic. In some embodiments, R^(C) isoxo, halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—S(O)NR₂, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, oran optionally substituted C₁₋₆ aliphatic. In some embodiments, R^(C) isoxo, halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—S(O)NR₂, or an optionally substituted C₁₋₆ aliphatic. In someembodiments, R^(C) is oxo, halogen, —CN, —OR, —SR, —S(O)₂R, —S(O)R, oran optionally substituted C₁₋₆ aliphatic. In some embodiments, R^(C) isoxo, —OR, —S(O)₂R, or an optionally substituted C₁₋₆ aliphatic.

In some embodiments, R^(C) is methyl.

In some embodiments, R^(C) is selected from those depicted in Table 1,below.

As defined generally above, each R is independently hydrogen, or anoptionally substituted group selected from C₁₋₆ aliphatic; phenyl;naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; a3-7 membered saturated or partially unsaturated monocyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur; a 7-12 membered saturated or partially unsaturatedbicyclic heterocyclic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; or:

-   -   two R groups on the same nitrogen are taken together with the        nitrogen to form an optionally substituted 4-7 membered        monocyclic saturated, partially unsaturated, or heteroaryl ring        having, in addition to the nitrogen, 0-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen, or an optionally substituted groupselected from C₁₋₆ aliphatic; phenyl; naphthalenyl; an 8-10 memberedbicyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, two R groups on the same nitrogen are takentogether with the nitrogen to form an optionally substituted 4-7membered monocyclic saturated, partially unsaturated, or heteroaryl ringhaving, in addition to the nitrogen, 0-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is anoptionally substituted group selected from C₁₋₆ aliphatic; phenyl;naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; a3-7 membered saturated or partially unsaturated monocyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur; a 7-12 membered saturated or partially unsaturatedbicyclic heterocyclic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, R is an optionally substituted group selected fromC₁₋₆ aliphatic; phenyl; and naphthalenyl. In some embodiments, R is anoptionally substituted group selected from an 8-10 membered bicyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen, an optionally substituted C₁₋₆aliphatic, or two R groups on the same nitrogen are taken together withthe nitrogen to form an optionally substituted 4-7 membered monocyclicsaturated, partially unsaturated, or heteroaryl ring having, in additionto the nitrogen, 0-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, R is hydrogen, an optionallysubstituted C₁₋₆ aliphatic, or two R groups on the same nitrogen aretaken together with the nitrogen to form an optionally substituted 4-7membered monocyclic saturated ring having, in addition to the nitrogen,0-1 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R is hydrogen or an optionally substitutedC₁₋₆ aliphatic. In some embodiments, R is hydrogen or an optionallysubstituted C₁₋₃ aliphatic.

In some embodiments, R is selected from those depicted in Table 1,below.

As defined generally above, R¹ is Cy¹.

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined generally above, Cy¹ is phenyl; a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; a 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated orpartially unsaturated bicyclic heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein Cy¹ issubstituted with p instances of R^(1A).

In some embodiments, Cy¹ is phenyl, substituted with p instances ofR^(1A). In some embodiments, Cy¹ is a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; substituted with p instances of R^(1A). In someembodiments, Cy¹ is an 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur;substituted with p instances of R^(1A). In some embodiments, Cy¹ is a3-7 membered saturated or partially unsaturated monocyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur; substituted with p instances of R^(1A). In someembodiments, Cy¹ is a 3-7 membered saturated or partially unsaturatedmonocyclic carbocyclic ring; substituted with p instances of R^(1A). Insome embodiments, Cy¹ is a 7-12 membered saturated or partiallyunsaturated bicyclic heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; substitutedwith p instances of R^(1A).

In some embodiments, Cy¹ is phenyl or a 3-7 membered saturated orpartially unsaturated monocyclic carbocyclic ring; wherein Cy¹ issubstituted with p instances of R^(1A). In some embodiments, Cy¹ is a5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; an 8-10membered bicyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora 7-12 membered saturated or partially unsaturated bicyclic heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; wherein Cy¹ is substituted with p instances ofR^(1A). In some embodiments, Cy¹ is a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; or an 8-10 membered bicyclic heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; wherein Cy¹ is substituted with p instances of R^(1A). In someembodiments, Cy¹ is a 3-7 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturatedor partially unsaturated bicyclic heterocyclic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein Cy¹ is substituted with p instances of R^(1A).

In some embodiments, Cy¹ is phenyl; a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; a 3-7 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated orpartially unsaturated monocyclic carbocyclic ring; wherein Cy¹ issubstituted with p instances of R^(1A). In some embodiments, Cy¹ is an8-10 membered bicyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; or a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; wherein Cy¹ is substituted with p instances of R^(1A).

In some embodiments, Cy¹ is phenyl; a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; wherein Cy¹ is substituted with pinstances of R^(1A). In some embodiments, Cy¹ is phenyl; a 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; or a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein Cy¹ is substituted with p instances of R^(1A). In someembodiments, Cy¹ is phenyl or a 5-6 membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; wherein Cy¹ is substituted with p instances of R^(1A).

In some embodiments, Cy¹ is phenyl; a 6 membered monocyclic heteroarylring having 1-2 nitrogen atoms; or a 6 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 nitrogen atoms;wherein Cy¹ is substituted with p instances of R^(1A). In someembodiments, Cy¹ is phenyl or a 6 membered monocyclic heteroaryl ringhaving 1-2 nitrogen atoms; wherein Cy¹ is substituted with p instancesof R^(1A). In some embodiments, Cy¹ is phenyl or pyridyl, substitutedwith p instances of R^(1A). In some embodiments, Cy¹ is pyridyl,substituted with p instances of R^(1A).

In some embodiments, Cy¹ is selected from the following:

In some embodiments, Cy¹ is selected from the following:

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is

In some embodiments, Cy¹ is substituted with 0-2 instances of R^(A) and1 instance of R^(B). In some embodiments, Cy¹ is substituted with 0-1instances of R^(A) and 1 instance of R^(B).

In some embodiments, Cy¹ together with its R^(1A) substituents isselected from the following:

In some embodiments, Cy¹ together with its R^(1A) substituents isselected from the following:

In some embodiments, Cy¹ is selected from those depicted in Table 1,below.

As defined generally above, each instance of R^(1A) is independentlyR^(A) or R^(B). In some embodiments, R^(1A) is R^(A). In someembodiments, R^(1A) is R^(B).

In some embodiments, R^(1A) is R^(A) or R^(B) selected from C₁₋₆aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; a3-7 membered saturated or partially unsaturated monocyclic carbocyclicring; and a 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; wherein each R^(B) is substituted with qinstances of R^(C); or two instances of R^(1A) are taken together toform an oxo.

In some embodiments, two instances of R^(1A) are taken together to forman oxo. In some embodiments, R^(1A) is R^(A) or R^(B) selected from C₁₋₆aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; a3-7 membered saturated or partially unsaturated monocyclic carbocyclicring; and a 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; wherein each R^(B) is substituted with qinstances of R^(C).

In some embodiments, R^(1A) is R^(A) or R^(B) selected from C₁₋₆aliphatic; phenyl; and a 3-7 membered saturated or partially unsaturatedmonocyclic carbocyclic ring; wherein each R^(B) is substituted with qinstances of R^(C). In some embodiments, R^(1A) is R^(A) or R^(B)selected from a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur;and a 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; wherein each R^(B) is substituted with qinstances of R^(C).

In some embodiments, R^(1A) is halogen; —CN; —OR; —NR₂; —C(O)NR₂; orR^(B) selected from C₁₋₆ aliphatic; phenyl; a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring; and a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein each R^(B) is substituted with q instances of R^(C).

In some embodiments, R^(1A) is halogen; —CN; —OR; —NR₂; —C(O)NR₂; orR^(B) selected from C₁₋₆ aliphatic; phenyl; and a 3-7 membered saturatedor partially unsaturated monocyclic carbocyclic ring; wherein each R^(B)is substituted with q instances of R^(C). In some embodiments, R^(1A) ishalogen; —CN; —OR; —NR₂; —C(O)NR₂; or R^(B) selected from a 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; and a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein each R^(B) is substituted with q instances of R^(C).

In some embodiments, at least one instance of R^(1A) is —C(O)NR₂ orR^(B). In some embodiments, at least one instance of R^(1A) is —C(O)NR₂.In some embodiments, at least one instance of R^(1A) is R^(B).

In some embodiments, at least one instance of R^(1A) is —C(O)NR₂ orR^(B) selected from a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; a3-7 membered saturated or partially unsaturated monocyclic carbocyclicring; and a 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; wherein each R^(B) is substituted with qinstances of R^(C). In some embodiments, at least one instance of R^(1A)is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 3-7 memberedsaturated or partially unsaturated monocyclic carbocyclic ring; or a 3-7membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur; each of which is substituted with q instances of R^(C).

In some embodiments, at least one instance of R^(1A) is —C(O)NR₂ orR^(B); wherein the two R groups are taken together with the nitrogen toform an optionally substituted 4-7 membered monocyclic saturated,partially unsaturated, or heteroaryl ring having, in addition to thenitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen,and sulfur. In some embodiments, at least one instance of R^(1A) is—C(O)NR₂; wherein the two R groups are taken together with the nitrogento form an optionally substituted 4-7 membered monocyclic saturated,partially unsaturated, or heteroaryl ring having, in addition to thenitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen,and sulfur.

In some embodiments, at least one instance of R^(1A) is —C(O)NR₂ orR^(B); wherein the two R groups are taken together with the nitrogen toform an optionally substituted 4-7 membered monocyclic saturated ringoptionally having, in addition to the nitrogen, one heteroatom selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, at least oneinstance of R^(1A) is —C(O)NR₂; wherein the two R groups are takentogether with the nitrogen to form an optionally substituted 4-7membered monocyclic saturated ring optionally having, in addition to thenitrogen, one heteroatom selected from nitrogen, oxygen, and sulfur.

In some embodiments, at least one instance of R^(1A) is —C(O)NR₂ orR^(B) selected from a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur; a3-7 membered saturated or partially unsaturated monocyclic carbocyclicring; and a 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; wherein each R^(B) is substituted with qinstances of R^(C); and wherein the two R groups are taken together withthe nitrogen to form an optionally substituted 4-7 membered monocyclicsaturated ring optionally having, in addition to the nitrogen, oneheteroatom selected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(1A) is selected from the following:

or two instances of R^(1A) are taken together to form an oxo.

In some embodiments, R¹ is selected from the following:

In some embodiments, R^(1A) is selected from those depicted in Table 1,below.

As defined generally above, R² is C₁₋₆ aliphatic; phenyl; a 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; a 3-7 membered saturated or partially unsaturatedmonocyclic carbocyclic ring; a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; or a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; each of which is substituted by q instances of R^(C).

In certain embodiments, R² is C₁₋₆ aliphatic which is substituted by qinstances of R^(C). In certain embodiments, R² is phenyl which issubstituted by q instances of R^(C). In certain embodiments, R² is a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur which is substituted by qinstances of R^(C). In certain embodiments, R² is an 8-10 memberedbicyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur which is substituted by q instances ofR^(C). In certain embodiments, R² is a 3-7 membered saturated orpartially unsaturated monocyclic carbocyclic ring which is substitutedby q instances of R^(C). In certain embodiments, R² is a 3-7 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfurwhich is substituted by q instances of R^(C). In certain embodiments, R²is a 7-12 membered saturated or partially unsaturated bicyclicheterocyclic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur which is substituted by q instances ofR^(C).

In some embodiments, R² is a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring, substituted by q instances ofR^(C). In some embodiments, R² is a 3-7 membered saturated monocycliccarbocyclic ring, substituted by q instances of R^(C). In someembodiments, R² is a 3-7 membered partially unsaturated monocycliccarbocyclic ring, substituted by q instances of R^(C). In someembodiments, R² is a 3-7 membered saturated or partially unsaturatedmonocyclic carbocyclic ring.

In some embodiments, R² is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, or cyclooctyl; each of which is independentlysubstituted by q instances of R^(C).

In some embodiments, R² is cyclopropyl.

In some embodiments, R² is

In some embodiments, R² together with its R^(C) substituents is

In some embodiments, R² is selected from those depicted in Table 1,below.

As defined generally above, R³ is —C(O)NH₂, —C(O)NHCH₃, or —C(O)NHCD₃.

In some embodiments, R³ is —C(O)NH₂. In some embodiments, R³ is—C(O)NHCH₃ or —C(O)NHCD₃. In some embodiments, R³ is —C(O)NHCH₃. In someembodiments, R³ is —C(O)NHCD₃.

In some embodiments, R³ is selected from those depicted in Table 1,below.

As defined generally above, p is 0, 1, 2, 3, or 4. In some embodiments,p is 0. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, pis 1. In some embodiments, p is 2. In some embodiments, p is 3. In someembodiments, p is 4.

In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2.In some embodiments, p is 1 or 3. In some embodiments, p is 2 or 3. Insome embodiments, p is 2 or 4. In some embodiments, p is 1, 2, or 4. Insome embodiments, p is 1, 3, or 4. In some embodiments, p is 2, 3, or 4.

In some embodiments, p is selected from those depicted in Table 1,below.

As defined generally above, q is 0, 1, 2, 3, or 4. In some embodiments,q is 0. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, qis 1. In some embodiments, q is 2. In some embodiments, q is 3. In someembodiments, q is 4.

In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2.In some embodiments, q is 1 or 3. In some embodiments, q is 2 or 3. Insome embodiments, q is 2 or 4. In some embodiments, q is 1, 2, or 4. Insome embodiments, q is 1, 3, or 4. In some embodiments, q is 2, 3, or 4.

In some embodiments, q is selected from those depicted in Table 1,below.

As defined generally above, r is 0 or 1. In some embodiments, r is 0. Insome embodiments, r is 1.

In some embodiments, r is selected from those depicted in Table 1,below.

In some embodiments, the present invention provides a compound offormula I′ wherein L¹ is a covalent bond and r is 1, thereby forming acompound of formula II:

or a pharmaceutically acceptable salt thereof, wherein each of X, R¹,R², and R³ is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula II wherein R is

thereby forming a compound of formula III, IV, or V respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X,R^(1A), R², R³, and p is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I′, II, III, IV, or V wherein r is 1 and X is CH, therebyforming a compound of formula I-a, II-a, III-a, IV-a, or V-arespectively:

or a pharmaceutically acceptable salt thereof, wherein each of L¹, R¹,R^(1A), R², R³, and p is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I′, II, III, IV, V, I-a, II-a, III-a, IV-a, or V-a wherein R³ is—C(O)NH₂.

In some embodiments, the present invention provides a compound offormula I′, II, III, IV, V, I-a, II-a, III-a, IV-a, or V-a wherein R³ is—C(O)NHCH₃ or —C(O)NHCD₃.

In some embodiments, the present invention provides a compound offormula I′ wherein L¹ is a covalent bond and r is 0, thereby forming acompound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein each of X, R¹,R², and R³ is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula VI wherein R¹ is

thereby forming a compound of formula VII, VIII, or IX respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X,R^(1A), R², R³, and p is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I′, VI, VII, VIII, or IX wherein r is 0 and X is CH, therebyforming a compound of formula I′-a, VI-a, VII-a, VIII-a, or IX-arespectively:

or a pharmaceutically acceptable salt thereof, wherein each of L¹, R¹,R^(1A), R², R³, and p is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I′-a, VI-a, VII-a, VIII-a, or IX-a wherein R³ is —C(O)NH₂.

In some embodiments, the present invention provides a compound offormula I′-a, VI-a, VII-a, VIII-a, or IX-a wherein R³ is —C(O)NHCH₃ or—C(O)NHCD₃.

In some embodiments, the present invention provides a compound offormula I′ wherein L¹ is a covalent bond, r is 0, and R² is

thereby forming a compound of formula X:

or a pharmaceutically acceptable salt thereof, wherein each of X, R¹,R², R³, R^(C), and q is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula X wherein R¹ is

thereby forming a compound of formula XI, XII, or XIII respectively:

or a pharmaceutically acceptable salt thereof, wherein each of X,R^(1A), R², R³, R^(C), p and q is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I′, X, XI, XII, or XIII wherein r is 0 and X is CH, therebyforming a compound of formula I″-a, X-a, XI-a, XII-a, or XIII-arespectively:

or a pharmaceutically acceptable salt thereof, wherein each of L¹, R¹,R^(1A), R², R³, R^(C), p and q is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I″-a, X-a, XI-a, XII-a, or XIII-a wherein R³ is —C(O)NH₂.

In some embodiments, the present invention provides a compound offormula I″-a, X-a, XI-a, XII-a, or XIII-a wherein R³ is —C(O)NHCH₃ or—C(O)NHCD₃.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Selected Compounds Compound Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof. Insome embodiments, the present invention provides a compound set forth inTable 1, above. In some embodiments, the present invention provides apharmaceutical composition comprising a compound set forth in Table 1above, or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier, excipient, or diluent.

In some embodiments, the present invention provides a compound offormula I or I′ as described above, wherein the compound is denoted as“A” as set forth in Table 2. In some embodiments, the present inventionprovides a compound of formula I or I′ as described above, wherein thecompound is denoted as “B” as set forth in Table 2. In some embodiments,the present invention provides a compound of formula I or I′ asdescribed above, wherein the compound is denoted as “C” as set forth inTable 2. In some embodiments, the present invention provides a compoundof formula I or I′ as described above, wherein the compound is denotedas “D” as set forth in Table 2. In some embodiments, the presentinvention provides a compound of formula I or I′ as described above,wherein the compound is denoted as “A” or “B” as set forth in Table 2.In some embodiments, the present invention provides a compound offormula I or I′ as described above, wherein the compound is denoted as“A” or “B” or “C” as set forth in Table 2. In some embodiments, thepresent invention provides a compound of formula I or I′ as describedabove, wherein the compound is denoted as “A” or “B” or “C” or “D” asset forth in Table 2.

In some embodiments, the present invention provides a compound offormula I or I′ as defined above, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition comprising a compound offormula I or I′ as defined above, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, adjuvant, or vehiclefor use as a medicament.

Without wishing to be bound by any particular theory, it is believedthat proximity of an inhibitor compound, or pendant moiety of aninhibitor compound, to the water of interest facilitates displacement ordisruption of that water by the inhibitor compound, or pendant moiety ofan inhibitor compound. In some embodiments, a water molecule displacedor disrupted by an inhibitor compound, or pendant moiety of an inhibitorcompound, is an unstable water molecule.

In certain embodiments, the method employs a complex comprising TYK2 andan inhibitor, wherein at least one unstable water of TYK2 is displacedor disrupted by the inhibitor. In some embodiments, at least twounstable waters selected are displaced or disrupted by the inhibitor.

4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit a TYK2 protein kinase, or amutant thereof, in a biological sample or in a patient. In certainembodiments, the amount of compound in compositions of this invention issuch that is effective to measurably inhibit a TYK2 protein kinase, or amutant thereof, in a biological sample or in a patient. In certainembodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof a TYK2 protein kinase, or a mutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of kinase activity of one or more enzymes. In someembodiments the kinase inhibited by the compounds and methods of theinvention is TYK2

TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs)family of protein kinases. The mammalian JAK family consists of fourmembers, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, areintegral to cytokine signaling. TYK2 associates with the cytoplasmicdomain of type I and type II cytokine receptors, as well as interferontypes I and III receptors, and is activated by those receptors uponcytokine binding. Cytokines implicated in TYK2 activation includeinterferons (e.g. IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, andIFN-ζ ((also known as limitin), and interleukins (e.g. IL-4, IL-6,IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M,ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-likecytokine, and LIF). Velasquez et al., “A protein kinase in theinterferon α/β signaling pathway,” Cell (1992) 70:313; Stahl et al.,“Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6βreceptor components,” Science (1994) 263:92; Finbloom et al., “IL-10induces the tyrosine phosphorylation of Tyk2 and Jak1 and thedifferential assembly of Stat1 and Stat3 complexes in human T cells andmonocytes,” J. Immunol. (1995) 155:1079; Bacon et al., “Interleukin 12(IL-12) induces tyrosine phosphorylation of Jak2 and Tyk2: differentialuse of Janus family kinases by IL-2 and IL-12,” J. Exp. Med. (1995)181:399; Welham et al., “Interleukin-13 signal transduction inlymphohemopoietic cells: similarities and differences in signaltransduction with interleukin-4 and insulin,” J. Biol. Chem. (1995)270:12286; Parham et al., “A receptor for the heterodimeric cytokineIL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit,IL-23R,” J. Immunol. (2002) 168:5699. The activated TYK2 then goes on tophosphorylate further signaling proteins such as members of the STATfamily, including STAT1, STAT2, STAT4, and STAT6.

TYK2 activation by IL-23, has been linked to inflammatory bowel disease(IBD), Crohn's disease, and ulcerative colitis. Duerr et al., “AGenome-Wide Association Study Identifies IL23R as an Inflammatory BowelDisease Gene,” Science (2006) 314:1461-1463. As the downstream effectorof IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis,and Behçet's disease. Cho et al., “Genomics and the multifactorialnature of human auto-immune disease,” N. Engl. J. Med (2011)365:1612-1623; Cortes et al., “Identification of multiple risk variantsfor ankylosing spondylitis through high-density genotyping ofimmune-related loci,” Nat. Genet. (2013) 45(7):730-738; Remmers et al.,“Genome-wide association study identifies variants in the MHC class I,IL10, and IL23R-IL12RB2 regions associated with Behçet's disease,” Nat.Genet. (2010) 42:698-702. A genome-wide association study of 2,622individuals with psoriasis identified associations between diseasesusceptibility and TYK2. Strange et al., “A genome-wide associationstudy identifies new psoriasis susceptibility loci and an interactionbetween HLA-C and ERAP1,” Nat. Genet. (2010) 42:985-992. Knockout ortyrphostin inhibition of TYK2 significantly reduces both IL-23 andIL-22-induced dermatitis. Ishizaki et al., “Tyk2 is a therapeutic targetfor psoriasis-like skin inflammation,” Intl. Immunol. (2013), doi:10.1093/intimm/dxt062.

TYK2 also plays a role in respiratory diseases such as asthma, chronicobstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis.Goblet cell hyperplasia (GCH) and mucous hypersecretion is mediated byIL-13-induced activation of TYK2, which in turn activates STAT6. Zhanget al., “Docking protein Gab2 regulates mucin expression and goblet cellhyperplasia through TYK2/STAT6 pathway,” FASEB J. (2012) 26:1-11.

Decreased TYK2 activity leads to protection of joints from collagenantibody-induced arthritis, a model of human rheumatoid arthritis.Mechanistically, decreased Tyk2 activity reduced the production ofT_(h)1/T_(h)17-related cytokines and matrix metalloproteases, and otherkey markers of inflammation. Ishizaki et al., “Tyk2 deficiency protectsjoints against destruction in anti-type II collagen antibody-inducedarthritis in mice,” Intl. Immunol. (2011) 23(9):575-582.

TYK2 knockout mice showed complete resistance in experimental autoimmuneencephalomyelitis (EAE, an animal model of multiple sclerosis (MS)),with no infiltration of CD4 T cells in the spinal cord, as compared tocontrols, suggesting that TYK2 is essential to pathogenic CD4-mediateddisease development in MS. Oyamada et al., “Tyrosine Kinase 2 PlaysCritical Roles in the Pathogenic CD4 T Cell Responses for theDevelopment of Experimental Autoimmune Encephalomyelitis,” J. Immunol.(2009) 183:7539-7546. This corroborates earlier studies linkingincreased TYK2 expression with MS susceptibility. Ban et al.,“Replication analysis identifies TYK2 as a multiple sclerosissusceptibility factor,” Eur J. Hum. Genet. (2009) 17:1309-1313. Loss offunction mutation in TYK2, leads to decreased demyelination andincreased remyelination of neurons, further suggesting a role for TYK2inhibitors in the treatment of MS and other CNS demyelination disorders.

TYK2 is the sole signaling messenger common to both IL-12 and IL-23.TYK2 knockout reduced methylated BSA injection-induced footpadthickness, imiquimod-induced psoriasis-like skin inflammation, anddextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid-inducedcolitis in mice.

Joint linkage and association studies of various type I IFN signalinggenes with systemic lupus erythematosus (SLE, an autoimmune disorder),showed a strong, and significant correlation between loss of functionmutations to TYK2 and decreased prevalence of SLE in families withaffected members. Sigurdsson et al., “Polymorphisms in the TyrosineKinase 2 and Interferon Regulatory Factor 5 Genes Are Associated withSystemic Lupis Erythematosus,” Am. J. Hum. Genet. (2005) 76:528-537.Genome-wide association studies of individuals with SLE versus anunaffected cohort showed highly significant correlation between the TYK2locus and SLE. Graham et al., “Association of NCF2, IKZF1, TRF8, IFIH1,and TYK2 with Systemic Lupus Erythematosus,” PLoS Genetics (2011)7(10):e1002341.

TYK2 has been shown to play an important role in maintaining tumorsurveillance and TYK2 knockout mice showed compromised cytotoxic T cellresponse, and accelerated tumor development. However, these effects werelinked to the efficient suppression of natural killer (NK) and cytotoxicT lymphocytes, suggesting that TYK2 inhibitors would be highly suitablefor the treatment of autoimmune disorders or transplant rejection.Although other JAK family members such as JAK3 have similar roles in theimmune system, TYK2 has been suggested as a superior target because ofits involvement in fewer and more closely related signaling pathways,leading to fewer off-target effects. Simma et al. “Identification of anIndispensable Role for Tyrosine Kinase 2 in CTL-Mediated TumorSurveillance,” Cancer Res. (2009) 69:203-211.

However, paradoxically to the decreased tumor surveillance observed bySimma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL)indicate that T-ALL is highly dependent on IL-10 via TYK2 viaSTAT1-mediated signal transduction to maintain cancer cell survivalthrough upregulation of anti-apoptotic protein BCL2. Knockdown of TYK2,but not other JAK family members, reduced cell growth. Specificactivating mutations to TYK2 that promote cancer cell survival includethose to the FERM domain (G36D, S47N, and R425H), the JH2 domain(V731I), and the kinase domain (E957D and R1027H). However, it was alsoidentified that the kinase function of TYK2 is required for increasedcancer cell survival, as TYK2 enzymes featuring kinase-dead mutations(M978Y or M978F) in addition to an activating mutation (E957D) resultedin failure to transform. Sanda et al. “TYK2-STAT1-BCL2 PathwayDependence in T-Cell Acute Lymphoblastic Leukemia,” Cancer Disc. (2013)3(5):564-577.

Thus, selective inhibition of TYK2 has been suggested as a suitabletarget for patients with IL-10 and/or BCL2-addicted tumors, such as 70%of adult T-cell leukemia cases. Fontan et al. “Discovering What MakesSTAT Signaling TYK in T-ALL,” Cancer Disc. (2013) 3:494-496.

TYK2 mediated STAT3 signaling has also been shown to mediate neuronalcell death caused by amyloid-β (Aβ) peptide. Decreased TYK2phosphorylation of STAT3 following Aβ administration lead to decreasedneuronal cell death, and increased phosphorylation of STAT3 has beenobserved in postmorterm brains of Alzheimer's patients. Wan et al.“Tyk/STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death:Implications in Alzheimer's Disease,” J. Neurosci. (2010)30(20):6873-6881.

Inhibition of JAK-STAT signaling pathways is also implicated in hairgrowth, and the reversal of the hair loss associated with alopeciaareata. Xing et al., “Alopecia areata is driven by cytotoxic Tlymphocytes and is reversed by JAK inhibition,” Nat. Med. (2014) 20:1043-1049; Harel et al., “Pharmacologic inhibition of JAK-STAT signalingpromotes hair growth,” Sci. Adv. (2015) 1(9):e1500973.

Accordingly, compounds that inhibit the activity of TYK2 are beneficial,especially those with selectivity over JAK2. Such compounds shoulddeliver a pharmacological response that favorably treats one or more ofthe conditions described herein without the side-effects associated withthe inhibition of JAK2.

Even though TYK2 inhibitors are known in the art, there is a continuingneed to provide novel inhibitors having more effective or advantageouspharmaceutically relevant properties. For example, compounds withincreased activity, selectivity over other JAK kinases (especiallyJAK2), and ADMET (absorption, distribution, metabolism, excretion,and/or toxicity) properties. Thus, in some embodiments, the presentinvention provides inhibitors of TYK2 which show selectivity over JAK2.

The activity of a compound utilized in this invention as an inhibitor ofTYK2, or a mutant thereof, may be assayed in vitro, in vivo or in a cellline. In vitro assays include assays that determine inhibition of eitherthe phosphorylation activity and/or the subsequent functionalconsequences, or ATPase activity of activated TYK2, or a mutant thereof.Alternate in vitro assays quantitate the ability of the inhibitor tobind to TYK2. Inhibitor binding may be measured by radiolabeling theinhibitor prior to binding, isolating the inhibitor/TYK2 complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with TYK2 bound to known radioligands.Representative in vitro and in vivo assays useful in assaying a TYK2inhibitor include those described and disclosed in, e.g., each of whichis herein incorporated by reference in its entirety. Detailed conditionsfor assaying a compound utilized in this invention as an inhibitor ofTYK2, or a mutant thereof, are set forth in the Examples below.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are inhibitors of TYK2 and are therefore useful fortreating one or more disorders associated with activity of TYK2 ormutants thereof. Thus, in certain embodiments, the present inventionprovides a method for treating a TYK2-mediated disorder comprising thestep of administering to a patient in need thereof a compound of thepresent invention, or pharmaceutically acceptable composition thereof.

As used herein, the term “TYK2-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which TYK2 or a mutant thereof is known to play a role.Accordingly, another embodiment of the present invention relates totreating or lessening the severity of one or more diseases in whichTYK2, or a mutant thereof, is known to play a role. Such TYK2-mediateddisorders include but are not limited to autoimmune disorders,inflammatory disorders, proliferative disorders, endocrine disorders,neurological disorders and disorders associated with transplantation.

In some embodiments, the present invention provides a method fortreating one or more disorders, wherein the disorders are selected fromautoimmune disorders, inflammatory disorders, proliferative disorders,endocrine disorders, neurological disorders, and disorders associatedwith transplantation, said method comprising administering to a patientin need thereof, a pharmaceutical composition comprising an effectiveamount of a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the disorder is an autoimmune disorder. In someembodiments the disorder is selected from type 1 diabetes, cutaneouslupus erythematosus, systemic lupus erythematosus, multiple sclerosis,psoriasis, Behçet's disease, POEMS syndrome, Crohn's disease, ulcerativecolitis, and inflammatory bowel disease.

In some embodiments, the disorder is an inflammatory disorder. In someembodiments, the inflammatory disorder is rheumatoid arthritis, asthma,chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn'sdisease, ulcerative colitis, inflammatory bowel disease.

In some embodiments, the disorder is a proliferative disorder. In someembodiments, the proliferative disorder is a hematological cancer. Insome embodiments the proliferative disorder is a leukemia. In someembodiments, the leukemia is a T-cell leukemia. In some embodiments theT-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In someembodiments the proliferative disorder is polycythemia vera,myelofibrosis, essential or thrombocytosis.

In some embodiments, the disorder is an endocrine disorder. In someembodiments, the endocrine disorder is polycystic ovary syndrome,Crouzon's syndrome, or type 1 diabetes.

In some embodiments, the disorder is a neurological disorder. In someembodiments, the neurological disorder is Alzheimer's disease.

In some embodiments the proliferative disorder is associated with one ormore activating mutations in TYK2. In some embodiments, the activatingmutation in TYK2 is a mutation to the FERM domain, the JH2 domain, orthe kinase domain. In some embodiments the activating mutation in TYK2is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

In some embodiments, the disorder is associated with transplantation. Insome embodiments the disorder associated with transplantation istransplant rejection, or graft versus host disease.

In some embodiments the disorder is associated with type I interferon,IL-10, IL-12, or IL-23 signaling. In some embodiments the disorder isassociated with type I interferon signaling. In some embodiments thedisorder is associated with IL-10 signaling. In some embodiments thedisorder is associated with IL-12 signaling. In some embodiments thedisorder is associated with IL-23 signaling.

Compounds of the invention are also useful in the treatment ofinflammatory or allergic conditions of the skin, for example psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, cutaneous lupus erythematosus, systemic lupuserythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplasticpemphigus, epidermolysis bullosa acquisita, acne vulgaris, and otherinflammatory or allergic conditions of the skin.

Compounds of the invention may also be used for the treatment of otherdiseases or conditions, such as diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as ocular allergy, conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, diseasesaffecting the nose including allergic rhinitis, and inflammatory diseasein which autoimmune reactions are implicated or having an autoimmunecomponent or etiology, including autoimmune hematological disorders(e.g. hemolytic anemia, aplastic anemia, pure red cell anemia andidiopathic thrombocytopenia), cutaneous lupus erythematosus, systemiclupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma,Wegener granulamatosis, dermatomyositis, chronic active hepatitis,myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), irritable bowel syndrome, celiac disease, periodontitis,hyaline membrane disease, kidney disease, glomerular disease, alcoholicliver disease, multiple sclerosis, endocrine opthalmopathy, Grave'sdisease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis,multiple sclerosis, primary biliary cirrhosis, uveitis (anterior andposterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernalkeratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis,systemic juvenile idiopathic arthritis, cryopyrin-associated periodicsyndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis,glomerulonephritis (with and without nephrotic syndrome, e.g. includingidiopathic nephrotic syndrome or minal change nephropathy), chronicgranulomatous disease, endometriosis, leptospiriosis renal disease,glaucoma, retinal disease, ageing, headache, pain, complex regional painsyndrome, cardiac hypertrophy, musclewasting, catabolic disorders,obesity, fetal growth retardation, hyperchlolesterolemia, heart disease,chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia,Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis,hereditary periodic fever syndrome, asthma (allergic and non-allergic,mild, moderate, severe, bronchitic, and exercise-induced), acute lunginjury, acute respiratory distress syndrome, eosinophilia,hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silicainduced diseases, COPD (reduction of damage, airways inflammation,bronchial hyperreactivity, remodeling or disease progression), pulmonarydisease, cystic fibrosis, acid-induced lung injury, pulmonaryhypertension, polyneuropathy, cataracts, muscle inflammation inconjunction with systemic sclerosis, inclusion body myositis, myastheniagravis, thyroiditis, Addison's disease, lichen planus, Type 1 diabetes,or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic jubenileidiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome(CAPS), and osteoarthritis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is a T_(h)1 or T_(h)17mediated disease. In some embodiments the T_(h)17 mediated disease isselected from cutaneous lupus erythematosus, Systemic lupuserythematosus, Multiple sclerosis, and inflammatory bowel disease(including Crohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from Sjogren'ssyndrome, allergic disorders, osteoarthritis, conditions of the eye suchas ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernalconjunctivitis, and diseases affecting the nose such as allergicrhinitis.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of an autoimmune disorder, an inflammatory disorder, or aproliferative disorder, or a disorder commonly occurring in connectionwith transplantation.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex© and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

In one embodiment, the present invention provides a compositioncomprising a compound of formula I or I′ and one or more additionaltherapeutic agents. The therapeutic agent may be administered togetherwith a compound of formula I or I′, or may be administered prior to orfollowing administration of a compound of formula I or I′. Suitabletherapeutic agents are described in further detail below. In certainembodiments, a compound of formula I or I′ may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursbefore the therapeutic agent. In other embodiments, a compound offormula I or I′ may be administered up to 5 minutes, 10 minutes, 15minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following thetherapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a compound of formula I or I′ and one ormore additional therapeutic agents. Such additional therapeutic agentsmay be small molecules or recombinant biologic agents and include, forexample, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS)such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®),antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), methotrexate (Rheumatrex®), gold salts such as goldthioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin(Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine(Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®),cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab(Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a compound of formula I or I′ and one or more additionaltherapeutic agents selected from non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, sulfasalazine(Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) andchloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such asgold thioglucose (Solganal®), gold thiomalate (Myochrysine®) andauranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®),azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil(Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and“anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®),golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab(Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®) and “anti-IL-6” agents such astocilizumab (Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof acompound of formula I or I′ and one or more additional therapeuticagents selected from acetaminophen, non-steroidal anti-inflammatorydrugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®)and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® orHyalgan®) and monoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatingcutaneous lupus erythematosus or systemic lupus erythematosus comprisingadministering to a patient in need thereof a compound of formula I or I′and one or more additional therapeutic agents selected fromacetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,corticosteroids such as prednisone, prednisolone, methylprednisolone,hydrocortisone, and the like, antimalarials such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®),methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatingCrohn's disease, ulcerative colitis, or inflammatory bowel diseasecomprising administering to a patient in need thereof a compound offormula I or I′ and one or more additional therapeutic agents selectedfrom mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrhealssuch as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acidbinding agents such as cholestyramine, alosetron (Lotronex®),lubiprostone (Amitiza®), laxatives such as Milk of Magnesia,polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® andanticholinergics or antispasmodics such as dicyclomine (Bentyl®),anti-TNF therapies, steroids, and antibiotics such as Flagyl orciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a compoundof formula I or I′ and one or more additional therapeutic agentsselected from Singulair®, beta-2 agonists such as albuterol (Ventolin®HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol(Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate(Brethaire®), salmeterol xinafoate (Serevent®) and formoterol(Foradil®), anticholinergic agents such as ipratropium bromide(Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines suchas theophylline (Theo-Dur®, Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) andaminophylline, and IgE antibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a compound offormula I or I′ and one or more additional therapeutic agents selectedfrom beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA),levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate(Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate(Serevent®) and formoterol (Foradil®), anticholinergic agents such asipratropium bromide (Atrovent®) and tiotropium (Spiriva®),methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®,Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®,

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I or I′ and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYKinhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a compound of formula I or I′ and one or more additionaltherapeutic agents selected from rituximab (Rituxan®), cyclophosphamide(Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®),prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I or I′ and a Hedgehog(Hh) signaling pathway inhibitor. In some embodiments, the hematologicalmalignancy is DLBCL (Ramirez et al “Defining causative factorscontributing in the activation of hedgehog signaling in diffuse largeB-cell lymphoma” Leuk. Res. (2012), published online July 17, andincorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a compound of formula I or I′ and one ormore additional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a compound of formula I or I′ and one or more additionaltherapeutic agents selected from bortezomib (Velcade®), anddexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTKinhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor,a SYK inhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I or I′ and a BTKinhibitor, wherein the disease is selected from inflammatory boweldisease, arthritis, cutaneous lupus erythematosus, systemic lupuserythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura(ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis,Still's disease, juvenile arthritis, diabetes, myasthenia gravis,Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmunethyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis,Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylosis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia,celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenicpurpura, optic neuritis, scleroderma, primary biliary cirrhosis,Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,membranous glomerulonephropathy, endometriosis, interstitial cystitis,pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma,vulvodynia, a hyperproliferative disease, rejection of transplantedorgans or tissues, Acquired Immunodeficiency Syndrome (AIDS, also knownas HIV), type 1 diabetes, graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis, asthma,appendicitis, atopic dermatitis, asthma, allergy, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn'sdisease, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitissuppurativa, immunoglobulin A nephropathy, interstitial lung disease,laryngitis, mastitis, meningitis, myelitis myocarditis, myositis,nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis,parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, polymyositis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis,vasculitis, or vulvitis, B-cell proliferative disorder, e.g., diffuselarge B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia,B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrommacroglobulinemia, splenic marginal zone lymphoma, multiple myeloma(also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin'slymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodalmarginal zone B cell lymphoma, mantle cell lymphoma, mediastinal(thymic) large B cell lymphoma, intravascular large B cell lymphoma,primary effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoidgranulomatosis, breast cancer, prostate cancer, or cancer of the mastcells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma,systemic mastocytosis), bone cancer, colorectal cancer, pancreaticcancer, diseases of the bone and joints including, without limitation,rheumatoid arthritis, seronegative spondyloarthropathies (includingankylosing spondylitis, psoriatic arthritis and Reiter's disease),Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis,bone cancer, bone metastasis, a thromboembolic disorder, (e.g.,myocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, deep venousthrombosis), inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, cutaneous lupus erythematosus, systemic lupuserythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenilearthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura,Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto'sthyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease,scleraderma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I or I′ and a PI3Kinhibitor, wherein the disease is selected from a cancer, aneurodegenative disorder, an angiogenic disorder, a viral disease, anautoimmune disease, an inflammatory disorder, a hormone-related disease,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, chronic myelogenous leukemia(CML), chronic lymphocytic leukemia (CLL), liver disease, pathologicimmune conditions involving T cell activation, a cardiovasculardisorder, and a CNS disorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I or I′ and a PI3Kinhibitor, wherein the disease is selected from benign or malignanttumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cellcarcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, endometrium, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma or gastrointestinal cancer, especially colon carcinomaor colorectal adenoma or a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, (including, for example,non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termedHodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), cutaneous lupuserythematosus, systemic lupus erythematosus, rheumatoid arthritis,polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis,chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome,idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerativecolitis and Crohn's disease), endocrine opthalmopathy, Grave's disease,sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiplesclerosis, primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

In some embodiments the present invention provides a method of treatingor lessening the severity of a disease comprising administering to apatient in need thereof a compound of formula I or I′ and a Bcl-2inhibitor, wherein the disease is an inflammatory disorder, anautoimmune disorder, a proliferative disorder, an endocrine disorder, aneurological disorder, or a disorder associated with transplantation. Insome embodiments, the disorder is a proliferative disorder, lupus, orlupus nephritis. In some embodiments, the proliferative disorder ischronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin'sdisease, small-cell lung cancer, non-small-cell lung cancer,myelodysplastic syndrome, lymphoma, a hematological neoplasm, or solidtumor.

In some embodiments, the present invention provides a method of treatingor lessening the severity of a disease, comprising administering to apatient in need thereof a TYK2 pseudokinase (JH2) domain bindingcompound and a TYK2 kinase (JH1) domain binding compound. In someembodiments, the disease is an autoimmune disorder, an inflammatorydisorder, a proliferative disorder, an endocrine disorder, aneurological disorder, or a disorder associated with transplantation. Insome embodiments the JH2 binding compound is a compound of formula I orI′. Other suitable JH2 domain binding compounds include those describedin WO2014074660A1, WO2014074661A1, WO2015089143A1, the entirety of eachof which is incorporated herein by reference. Suitable JH1 domainbinding compounds include those described in WO2015131080A1, theentirety of which is incorporated herein by reference.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of anautoimmune disorder, an inflammatory disorder, a proliferative disorder,an endocrine disorder, a neurological disorder, or a disorder associatedwith transplantation. The exact amount required will vary from subjectto subject, depending on the species, age, and general condition of thesubject, the severity of the infection, the particular agent, its modeof administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity in a biological sample comprising thestep of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting TYK2, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound. In certainembodiments, the invention relates to a method of irreversiblyinhibiting TYK2, or a mutant thereof, activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

In another embodiment, the invention provides a method of selectivelyinhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In someembodiments, a compound of the present invention is more than 2-foldselective over JAK1/2/3. In some embodiments, a compound of the presentinvention is more than 5-fold selective over JAK1/2/3. In someembodiments, a compound of the present invention is more than 10-foldselective over JAK1/2/3. In some embodiments, a compound of the presentinvention is more than 50-fold selective over JAK1/2/3. In someembodiments, a compound of the present invention is more than 100-foldselective over JAK1/2/3.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of TYK2 (or a mutant thereof) activity in a biological sampleis useful for a variety of purposes that are known to one of skill inthe art. Examples of such purposes include, but are not limited to,blood transfusion, organ-transplantation, biological specimen storage,and biological assays.

Another embodiment of the present invention relates to a method ofinhibiting protein kinase activity in a patient comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting activity of TYK2, or a mutant thereof, in a patientcomprising the step of administering to said patient a compound of thepresent invention, or a composition comprising said compound. Accordingto certain embodiments, the invention relates to a method of reversiblyor irreversibly inhibiting one or more of TYK2, or a mutant thereof,activity in a patient comprising the step of administering to saidpatient a compound of the present invention, or a composition comprisingsaid compound. In other embodiments, the present invention provides amethod for treating a disorder mediated by TYK2, or a mutant thereof, ina patient in need thereof, comprising the step of administering to saidpatient a compound according to the present invention orpharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other therapeutic compounds. In some embodiments, theother therapeutic compounds are antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal©); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin. The term “aromatase inhibitor” as used hereinrelates to a compound which inhibits estrogen production, for instance,the conversion of the substrates androstenedione and testosterone toestrone and estradiol, respectively. The term includes, but is notlimited to steroids, especially atamestane, exemestane and formestaneand, in particular, non-steroids, especially aminoglutethimide,roglethimide, pyridoglutethimide, trilostane, testolactone,ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestaneis marketed under the trade name Aromasin™. Formestane is marketed underthe trade name Lentaron™. Fadrozole is marketed under the trade nameAfema™. Anastrozole is marketed under the trade name Arimidex™ Letrozoleis marketed under the trade names Femara™ or Femar™. Aminoglutethimideis marketed under the trade name Orimeten™. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™) daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™ Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the A×I receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, BTK and TEC family, and/or membersof the cyclin-dependent kinase family (CDK) including staurosporinederivatives, such as midostaurin; examples of further compounds includeUCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196;isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) orAT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibitingthe activity of protein-tyrosine kinase inhibitors, such as compoundswhich target, decrease or inhibit the activity of protein-tyrosinekinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostinsuch as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, C₁₋₁₀33, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), 5-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDCl25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MM1270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase, and Bcl-2 inhibitors.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PR064553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412. In some embodiments, the presentinvention provides a method of treating AML associated with an ITDand/or D835Y mutation, comprising administering a compound of thepresent invention together with a one or more FLT3 inhibitors. In someembodiments, the FLT3 inhibitors are selected from quizartinib (AC220),a staurosporine derivative (e.g. midostaurin or lestaurtinib),sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302,NMS-P948, AST-487, G-749, SB-1317, 5-209, SC-110219, AKN-028,fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3inhibitors are selected from quizartinib, midostaurin, lestaurtinib,sorafenib, and sunitinib.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene),VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2aagonists; A2b antagonists; and beta-2 adrenoceptor agonists such asalbuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol and pharmaceuticallyacceptable salts thereof. Suitable bronchodilatory drugs includeanticholinergic or antimuscarinic compounds, in particular ipratropiumbromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), andglycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein. Additional compounds of theinvention were prepared by methods substantially similar to thosedescribed herein in the Examples and methods known to one skilled in theart.

General Procedure A (Suzuki Coupling)

Synthesis of Compound 1.1

Argon was purged for 15 min through a stirring solution of Core A (0.2g, 0.313 mmol, 1.0 eq), phenyl boronic acid (0.049 g, 0.406 mmol, 1.3eq) and potassium carbonate (0.107 g, 0.782 mmol, 2.5 eq) in1,4-dioxane:water (10 mL, 9:1).[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.022 g,0.0313 mmol, 0.1 eq) was added to it and further purging done for 10min. Reaction was allowed to stir at 100° C. for 5 h. After completionof reaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain 1.1. (0.140 g, 75.93%). MS (ES): m/z 588.19 [M+H]⁺.

General Procedure B (Deprotection with Triflic Acid)

Synthesis of Compound 1.2

To a cooled solution of 1.1 (0.140 g, 0.238 mmol, 1.0 eq) indichloromethane (2 mL), triflic acid (1 mL) was added at 0° C. Reactionmixture was stirred at same temperature for 10 min. After completion ofreaction, reaction mixture was transferred into 1N sodium hydroxidesolution and product was extracted with dichloromethane. Organic layerwas combined, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified bytrituration with diethyl ether to a obtain 1.2. (0.063 g, 98.94%), MS(ES): m/z 268.10 [M+H]⁺.

General Procedure C (Amide Formation with Acid Chloride)

Synthesis of Compound 1.3

To a solution of compound 1.2 (0.070 g, 0.26 mmol, 1.0 eq) intetrahydrofuran (2 mL) at 0° C. was added triethylamine (0.078 g, 0.78mmol, 3.0 eq) and stirred for 10 min followed by addition ofcyclopropanecarbonyl chloride (0.041 g, 0.39 mmol, 1.5 eq). The reactionmixture was stirred at 0° C. for 30 min. After completion of reaction,reaction mixture was transferred into ice cold water and product wasextracted with ethyl acetate. Organic layer was combined, washed withsaturated sodium bicarbonate solution followed by brine solution andwater, dried over sodium sulfate and concentrated under reduced pressureto obtain crude material. This was further purified by columnchromatography using 20% ethyl acetate in hexane to obtain 1.3. (0.025g, Yield: 28.46%). MS (ES): m/z 336.13 [M+H]⁺.

General Procedure D (Amide Formation Mediated by Trimethylaluminum)

Synthesis of Compound I-1

To a solution of compound 1.3 (0.025 g, 0.074 mmol, 1.0 eq) andmethylamine (2M in THF, 0.11 mL, 0.22 mmol, 3.0 eq) in tetrahydrofuran(2 mL) was added N,N-diisopropylethylamine (0.028 g, 0.22 mmol, 3.0 eq)followed by trimethylaluminum (2M, 0.18 mL, 0.37 mmol, 5.0 eq) at 0° C.Reaction mixture was stirred at 70° C. for 5 h. After completion ofreaction, reaction mixture was transferred to ice cold water and productwas extracted with ethyl acetate. Organic layer was combined, washedwith brine solution, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bycolumn chromatography eluting with 2.5% methanol in dichloromethane toobtain I-1 (0.010 g, 40.12%). MS (ES): m/z 335.30 [M+H]⁺.

General Procedure E (Stille Coupling)

Synthesis of Compound 10.6

Argon was purged for 15 min through a stirring mixture of Core C (0.9 g,1.12 mmol, 1.0 eq), compound 10.5 (0.368 g, 1.45 mmol, 1.0 eq), andcesium fluoride (0.338 g, 2.24 mmol, 2.0 eq) in dimethylformamide (10mL). Copper(I) iodide (0.021 g, 1.11 mmol, 0.1 eq) andtetrakis(triphenylphosphine)palladium(0) (0.064 g, 0.056 mmol, 0.05 eq)was added to it and further purging done for 10 min. Reaction mixturewas allowed to stir at 100° C. for 1 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain 10.6. (0.120 g, 15.57%). MS (ES): m/z 686.19 [M+H]⁺.

General Procedure F (Boronate Ester Preparation—Pd₂(dba)₃ and Ligand)

Synthesis of Compound 7.3

To a solution of 7.2 (1.3 g, 5.48 mmol, 1.0 eq) in 1,4-dioxane (48 mL)was added bis(pinacolato)diboron (1.6 g, 6.57 mmol, 1.2 eq) andpotassium acetate (1.0 g, 10.96 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 min. under argon atmosphere, thentris(dibenzylideneacetone)dipalladium(0) (0.250 g, 0.274 mmol, 0.05 eq)and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.312 g, 0.54 mmol,0.1 eq) were added, again degassed for 5 min. The reaction was stirredat 110° C. for 4 h. After completion of reaction, reaction mixture wascooled to room temperature, transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by combiflash using 3% methanol in dichloromethane as eluant to obtain pure 7.3.(1.0 g, 64.18%). MS (ES): m/z 285.17 [M+H]⁺.

General Procedure G (Boronate Ester Preparation—Pd(dppf)Cl₂)

Synthesis of Compound 27.1

To a solution of 1-bromo-3-nitrobenzene (1.0 g, 4.95 mmol, 1.0 eq) indimethyl sulfoxide (20 mL) was added bis(pinacolato)diboron (1.5 g, 5.94mmol, 1.2 eq) and potassium acetate (0.970 g, 9.9 mmol, 2.0 eq). Thereaction mixture was degassed for 10 min. under argon atmosphere, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.358 g,0.49 mmol, 0.1 eq) was added, again degassed for 5 min. The reaction wasstirred at 90° C. for 4 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 3% methanol in dichloromethane as eluantto obtain pure 27.1. (0.32 g, Yield: 25.95%). MS (ES): m/z 250.12[M+H]⁺.

General Procedure H (Amide Coupling with HATU)

Synthesis of Compound I-24

To a solution of compound 24.9 (0.060 g, 0.13 mmol, 1.0 eq), inN,N-dimethylformamide (2 mL) was added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.098 g, 0.26 mmol, 2.0 eq) and stirred atroom temperature for 15 min. To this added diisopropylethylamine (0.050g, 0.39 mmol, 3.0 eq) followed by addition of methylamine (2M in THE0.078 mL, 0.13 mmol, 1.2 eq). The reaction mixture was stirred at roomtemperature for 5 min. After completion of reaction, reaction mixturewas transferred into water and product was extracted with ethyl acetate.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography and thecompound was eluted in 40% ethyl acetate in hexane to obtain I-24 (0.030g, Yield: 48.54%). MS (ES): m/z 448.37 [M+H]⁺.

Preparation of Core A: Methyl7-(dibenzylamino)-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxylate

Synthesis of Compound A.2

To a solution of compound A.1 (25.0 g, 105.48 mmol, 1.0 eq) intetrahydrofuran (800 mL) was added N,N-dibenzyl amine (33.85 g, 316.44mmol, 3.0 eq) and triethylamine (31.96 g, 316.44 mmol, 3.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was transferred to ice cold water and productwas extracted with ethyl acetate. Organic layer was combined, washedwith brine solution, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bycolumn chromatography eluting with 2.5% methanol in dichloromethane toobtain A.2. (32 g, Yield: 76.31%). MS (ES): m/z 399.04 [M+H]⁺.

Synthesis of Compound A.3

To a solution of compound A.2 (10.0 g, 25.12 mmol, 1.0 eq) intetrahydrofuran (200 mL) was added vinyl magnesium bromide (1M in THF,75 mL, 75.36 mmol, 3.0 eq) at −78° C. The reaction mixture was stirredat −78° C. for 1 h. After completion of reaction, reaction mixture wastransferred to ice cold water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatographyeluting with 10% ethyl acetate in hexane to obtain A.3. (2.5 g, Yield:25.58%). MS (ES): m/z 393.07 [M+H]⁺.

Synthesis of Compound A.4

carbon monoxide was purged for 15 min through a stirred solution ofcompound A.3 (1.5 g, 3.82 mmol, 1.0 eq) in methanol (70 mL) followed byaddition of triethylamine (1.1 g, 11.46 mmol, 3.0 eq) and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, complexwith dichloromethane (0.310 g, 0.38 mmol, 0.1 eq). Further purging donefor 10 min and reaction mixture was allowed to stir at 100° C. for 5 h.After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain A.4. (1.0 g, 73.93%). MS(ES): m/z 372.17 [M+H]⁺.

Synthesis of Compound A.5

To a suspension of sodium hydride (0.131 g, 5.38 mmol, 2.0 eq) intetrahydrofuran (10 mL) was added a solution of compound A.4 (1.0 g,2.69 mmol, 1.0 eq) in tetrahydrofuran (10 mL) (1.0 g, 2.69 mmol, 1.0 eq)dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 minand phenyl sulfonyl chloride (0.710 g, 4.03 mmol, 1.5 eq) was addedslowly dropwise. The reaction mixture was stirred at room temperaturefor 1 h. After completion of reaction, reaction mixture was transferredto ice cold water and product was extracted with ethyl acetate. Organiclayer was combined, washed with brine solution, dried over sodiumsulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography elutingwith 15% ethyl acetate in hexane to obtain A.5. (0.800 g, Yield:58.08%). MS (ES): m/z 512.16 [M+H]⁺.

Synthesis of Core A

To the solution of compound A.5 (0.8 g, 1.56 mmol, 1.0 eq) intetrahydrofuran (10 mL) was added lithium diisopropylamide (2.0M, 2.34mL, 4.68 mmol, 3.0 eq) at −78° C. The reaction mixture was stirred at−78° C. for 1 h. Then a solution of iodine (0.475 g, 1.87 mmol, 2.0 eq)in tetrahydrofuran (2 mL) was added to reaction mixture and stirred for2 h at same temperature. After completion of reaction, reaction mixturewas transferred to ice cold water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatographyeluting with 7% ethyl acetate in hexane to obtain Core A. (0.620 g,Yield: 63.39%). MS (ES): m/z 626.06 [M+H]⁺.

Preparation of Core B:(7-(dibenzylamino)-4-(methylcarbamoyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)boronicAcid

Synthesis of Compound B.1

To a solution of compound A.4 (8.0 g, 21.56 mmol, 1.0 eq) indichloromethane (80 mL) were added di-tert-butyl dicarbonate (8.4 g,38.80 mmol, 1.8 eq) and 4-dimethylaminopyridine (0.263 g, 2.15 mmol, 0.1eq) and stirred at room temperature for 4 h. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and compound was eluted in 20% ethyl acetate in hexane toobtain pure B.1. (7.5 g, 73.85%). MS (ES): m/z 472.22 [M+H]⁺.

Synthesis of Compound B.2

To a solution of compound B.1 (7.0 g, 14.86 mmol, 1.0 eq) intetrahydrofuran (170 mL) was added lithium diisopropylamide (2.0M, 14.8mL, 29.72 mmol, 3.0 eq) at −78° C. The reaction was stirred at −78° C.for 1 h. Then a solution of triisopropyl borate (5.5 g, 29.72 mmol, 2.0eq) was added to reaction mixture. The reaction mixture was stirred for2 h at 0° C. After completion of reaction, reaction mixture wastransferred to ice cold water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatographyeluting with 7% ethyl acetate in hexane to obtain B.2. (4.1 g, 66.51%).MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound B.3

To a solution of compound B.2 (1.0 g, 2.40 mmol, 1.0 eq), in methanol(10 mL) was added sodium hydroxide (0.480 g, 12 mmol, 5 eq). Thereaction was stirred at 60° C. for 6 h. After completion of reaction,reaction mixture was concentrated under reduced pressure to obtainresidue. To this added water and acidified with 1N hydrochloric acid toadjust pH-6-6.5 at 10° C. Product was extracted with dichloromethane.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography andcompound was eluted in 2.1% methanol in dichloromethane to obtain pureB.3. (0.650 g, 67.27%). MS (ES): m/z 402.16 [M+H]⁺.

Synthesis of Core B

To a solution of compound B.3 (0.650 g, 1.62 mmol, 1.0 eq), inN,N-dimethylformamide (7 mL) was added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (1.2 g, 3.24 mmol, 2.0 eq) and stirred atroom temperature for 15 min. To this added diisopropylethylamine (0.8mL, 4.86 mmol, 3.0 eq) followed by addition of methylamine (2M in THE1.05 mL, 2.10 mmol, 1.3 eq). The reaction mixture was stirred at roomtemperature for 5 min. After completion of reaction, reaction mixturewas transferred into water and product was extracted with ethyl acetate.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography and thecompound was eluted in 40% ethyl acetate in hexane to obtain Core B.(0.400 g, 59.60%). MS(ES): m/z 415.19 [M+H]⁺.

Preparation of Core C: Methyl7-(dibenzylamino)-1-(phenylsulfonyl)-2-(tributylstannyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxylate

Synthesis of Core C

To a solution of compound A.5 (3.0 g, 5.87 mmol, 1.0 eq) intetrahydrofuran (30 mL) was added lithium diisopropylamide (2.0M, 8.8mL, 17.61 mmol, 3.0 eq) dropwise at −78° C. The reaction mixture wasstirred at same temperature for 30 min. Then tributyltin chloride (1.90mL, 7.04 mmol, 1.2 eq) was added dropwise to the reaction mixture andstirred for 1 h at same temperature. After completion of reaction,reaction mixture was transferred into ice cold water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography eluting with 7% ethyl acetate in hexane to obtain Core C.(3.1 g, Yield: 66.03%). MS (ES): m/z 801.26 [M+H]⁺.

Example 1:7-(cyclopropanecarboxamido)-N-methyl-2-phenyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-1)

Synthesis of Compound 1.1

The compound was synthesized from Core A and phenylboronic acid usingGeneral Procedure A to obtain 1.1. (0.140 g, 75.93%). MS (ES): m/z588.19 [M+H]⁺.

Synthesis of Compound 1.2

The compound was synthesized from compound 1.1 using General Procedure Bto obtain 1.2. (0.063 g, 98.94%), MS (ES): m/z 268.10 [M+H]⁺.

Synthesis of Compound 1.3

The compound was synthesized from compound 1.2 using General Procedure Cto obtain 1.3. (0.025 g, Yield: 28.46%). MS (ES): m/z 336.13 [M+H]⁺.

Synthesis of Compound I-1

The compound was synthesized from compound 1.3 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-1 (0.010 g, 40.12%). MS (ES): m/z 335.30 [M+H]⁺ LCMS purity: 96.55%,HPLC purity: 97.65%, ¹H NMR (DMSO-d₆, 400 MHZ): 8.34 (bs, 1H), 8.29 (s,1H), 7.89 (bs, 1H), 7.87 (bs, 1H), 7.56-7.52 (t, J=7.6 Hz, 2H),7.46-7.42 (t, J=7.6 Hz, 1H), 7.36 (s, 1H), 2.85-2.84 (d, J=4.4 Hz, 3H),1.47 (s, 2H), 1.35-1.34 (d, J=7.2 Hz, 3H), 0.99 (bs, 2H).

Example 2:7-(cyclopropanecarboxamido)-N-methyl-2-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-2)

Synthesis of Compound 2.2

To a solution of compound 2.1 (3.0 g, 13.39 mmol, 1.0 eq) indimethylformamide (30 mL), was added methyl iodide (2.0 g, 14.72 mmol,1.1 eq). Sodium hydride (0.642 g, 26.78 mmol, 2 eq) was added at 0° C.Reaction mixture was stirred at room temperature for 2 h. Aftercompletion of reaction, reaction mixture was transferred into ice,stirred and extracted with diethyl ether. Organic layer was combined,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by distillation toobtain pure 2.2. (2.7 g, Yield: 84.70%). MS (ES): m/z 237.99 [M+H]⁺.

Synthesis of Compound 2.3

To a solution of compound 2.2 (0.8 g, 3.36 mmol, 1.0 eq) in 1,4-dioxane(30 mL) was added bis(pinacolato)diboron (1.0 g, 4.03 mmol, 1.2 eq) andpotassium acetate (0.659 g, 6.72 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 min. under argon atmosphere, thentris(dibenzylideneacetone)dipalladium(0) (0.153 g, 0.016 mmol, 0.05 eq)and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.159 g, 0.033mmol, 0.1 eq) were added, again degassed for 5 min. The reaction wasstirred at 100° C. for 4 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 3% methanol in dichloromethane as eluantto obtain pure 2.3 (0.7 g, 73.06%). MS(ES): m/z 286.17 [M+H]⁺.

Synthesis of Compound 2.4

The compound was synthesized from Core A and compound 2.3 using GeneralProcedure A to obtain 2.4. (0.210 g, 84.58%), MS (ES): m/z 528.22[M+H]⁺.

Synthesis of Compound 2.5

The compound was synthesized from compound 2.4 using General Procedure Bto obtain 2.5. (0.1 g, 72.12%), MS (ES): m/z 349.14 [M+H]⁺.

Synthesis of Compound 2.6

The compound was synthesized from compound 2.5 using General Procedure Cto obtain 2.6. (0.070 g, 58.56%), MS (ES): m/z 417.16 [M+H]⁺.

Synthesis of Compound I-2

The compound was synthesized from compound 2.6 and methylamine usingGeneral Procedure D. This was further purified by column chromatographyeluting with 2.5% methanol in dichloromethane to obtain I-2 (0.030 g,42.96%), MS (ES): m/z 416.38 [M+H]⁺ LCMS purity: 100%, HPLC purity:99.87%, ¹H NMR (DMSO-d₆, 400 MHZ): 8.61 (bs, 1H), 8.46 (bs, 1H),8.37-8.36 (d, J=4.4 Hz, 1H), 8.33 (s, 1H), 8.07-8.05 (d, J=8 Hz, 1H),7.91-7.89 (d, J=7.6 Hz, 1H), 7.67-7.63 (t, J=8 Hz, 1H), 7.42 (s, 1H),3.98 (s, 4H), 3.58 (s, 1H), 2.87-2.86 (d, J=4.4 Hz, 4H), 1.01 (bs, 2H),0.96-0.94 (d, J=7.6 Hz, 2H).

Example 3:7-(cyclopropanecarboxamido)-N-(methyl-d₃)-2-phenyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-3)

Synthesis of Compound I-3

To a solution of compound 1.3 (0.050 g, 0.14 mmol, 1.0 eq) andmethyl-d₃-amine hydrochloride (0.029 g, 0.42 mmol, 3.0 eq) intetrahydrofuran (2 mL) was added N,N-diisopropylethylamine (0.054 g,0.42 mmol, 3.0 eq) followed by trimethylaluminum (2M, 0.35 mL, 0.7 mmol,5.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. Thematerial was further purified by column chromatography eluting with 2.5%methanol in dichloromethane to obtain I-3 (0.027 g, 53.67%), MS (ES):338.38 [M+H]⁺ LCMS purity: 100%, HPLC purity: 99.52%, ¹H NMR (DMSO-d₆,400 MHZ): 11.53 (bs, 1H), 11.10 (bs, 1H), 7.94-7.93 (d, J=5.6 Hz, 1H),7.83 (s, 1H), 7.50-7.49 (d, J=4.4 Hz, 4H), 7.41-7.38 (m, 1H), 7.34-7.33(d, J=5.6 Hz, 1H), 2.20 (bs, 1H), 1.92 (s, 2H), 0.97 (bs, 1H), 0.94-0.92(m, 1H).

Example 4:7-(cyclopropanecarboxamido)-2-(2-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-4)

Synthesis of Compound 4.2

The compound was synthesized from Core A and compound 4.1 using GeneralProcedure A to obtain 4.2. (0.160 g, Yield: 73.66%), MS (ES): m/z 603.20[M+H]⁺.

Synthesis of Compound 4.4

To a solution of 4.2 (0.430 g, 0.93 mmol, 1.0 eq) in pyridine (4 mL) wasadded compound 4.3 (0.197 g, 1.11 mmol, 1.2 eq) at 0° C. The reactionmixture was stirred at room temperature for 3 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography eluting with 25% ethylacetate in hexane to obtain 4.4.(0.320 g, Yield: 46.21%). MS (ES): m/z 744.17 [M+H]⁺.

Synthesis of Compound 4.5

To a solution of 4.4 (0.320 g, 0.43 mmol, 1.0 eq) in dimethylformamide(3 mL) was added potassium carbonate (0.178 g, 1.29 mmol, 3.0 eq) atroom temperature. The reaction mixture was degassed for 10 min andheated at 50° C. for 8 h. After completion of reaction, reaction mixturewas transferred to ice cold water and product was extracted withethylacetate. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography eluting with 20% ethylacetate in hexane to obtain 4.5.(0.260 g, Yield: 85.44%). MS (ES): m/z 707.20 [M+H]⁺.

Synthesis of Compound 4.6

The compound was synthesized from compound 4.5 using General Procedure Bto obtain 4.6. (0.1 g, Yield: 70.35%), MS (ES): m/z 387.11 [M+H]⁺.

Synthesis of Compound 4.7

The compound was synthesized from compound 4.6 using General Procedure Cto obtain 4.7. (0.064 g, 54.41%), MS (ES): m/z 455.13 [M+H]⁺.

Synthesis of Compound I-4

The compound was synthesized from compound 4.7 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-4 (0.025 g, 39.15%), MS (ES): 454.46 [M+H]⁺ LCMS purity: 100%, HPLCpurity: 98.36%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.77 (s, 1H), 11.29 (s, 1H),8.39-8.36 (m, 3H), 7.98-7.96 (m, 1H), 7.68-7.66 (m, 1H), 7.55-7.52 (m,1H), 7.40 (s, 1H), 3.68-3.64 (t, J=6.4 Hz, 2H), 3.55-3.51 (d, J=7.6 Hz,2H), 3.41-3.36 (m, 1H), 2.85-2.84 (d, J=4 Hz, 3H), 2.22 (bs, 1H),1.11-1.07 (t, J7.2 Hz, 2H), 0.95-0.93 (m, 3H).

Example 5:7-(cyclopropanecarboxamido)-N-methyl-2-(2-(1-(methylsulfonyl)cyclopropyl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-5)

Synthesis of Compound 5.2

To a solution of compound 5.1 (10.0 g, 46.29 mmol, 1.0 eq) indimethylformamide (100 mL) was added sodium methansulfinate (5.1 g,50.91 mmol, 1.1 eq). The reaction mixture was stirred at 60° C. for 1 h.After completion of reaction, reaction mixture was transferred intowater to obtain precipitate which was filtered and dried to obtain 5.2.(8.0 g, Yield: 80.30%), MS(ES): m/z 216.03 [M+H]⁺.

Synthesis of Compound 5.3

To a solution of compound 5.2 (8.0 g, 37.20 mmol, 1.0 eq) in toluene (80mL) was added 1,2-dibromoethane (10.4 g, 55.8 mmol, 1.5 eq) andtetra-n-butylammonium bromide (1.79 g, 5.58 mmol, 0.15 eq). The reactionmixture was stirred and aqueous sodium hydroxide (10N) (4.46 g, 111.6mmol, 3.0 eq) was added. The reaction mixture was stirred at 60° C. for16 h. After completion of reaction, reaction mixture was transferredinto water to obtain precipitate which was was filtered, washed withhexane and dried to obtain 5.3. (2.1 g, Yield: 23.42%), MS(ES): m/z242.04 [M+H]⁺.

Synthesis of Compound 5.4

To a solution of compound 5.3 (2.1 g, 8.71 mmol, 1.0 eq) in methanol (40ml), 10% palladium on charcoal (1.0 g) was added. Hydrogen was purgedthrough reaction mixture for 4 h at room temperature. After completionof reaction, reaction mixture was filtered through Celite-bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 5.4. (1.6 g, Yield: 87.00%). MS (ES): m/z212.07 [M+H]⁺.

Synthesis of Compound 5.5

To compound 5.4 (1.6 g, 7.58 mmol, 1.0 eq) was added hydrobromic acid(48% aq, 3.2 mL) dropwise at 0° C. Then a solution of sodium nitrite in5 mL water (1.0 g, 15.16 mmol, 2.0 eq) was added followed by acetone (13mL) at 0° C. Reaction mixture was stirred at 0° C. for 5 min and addcopper(I) bromide (2.1 g, 15.16 mmol, 2.0 eq). The reaction mixture wasstirred at 0° C. for 1 h. After completion of reaction, reaction mixturewas transferred into water and product was extracted with ethyl acetate.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography and thecompound was eluted in 7% ethyl acetate in hexane to obtain 5.5. (1.3 g,Yield: 62.39%). MS(ES): m/z 274.97 [M+H]⁺.

Synthesis of Compound 5.6

To a solution of compound 5.5 (0.5 g, 1.82 mmol, 1.0 eq) in drytetrahydrofuran (15 mL) was added n-butyllithium (1.6M in hexane, 1.25mL, 2.00 mmol, 1.1 eq) dropwise at −78° C. Then stirred reaction mixtureat same temperature for 15 min. Then after was added tributyltinchloride (1.14 g, 3.64 mmol, 2.0 eq) at −78° C. The reaction mixture wasstirred at −78° C. for 2 h. After completion of reaction, to thereaction mixture was added 1N hydrochloric acid and reaction mixturebrought to room temperature and extracted with ethyl acetate. Organiclayer was combined, washed with brine solution, dried over sodiumsulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography and thecompound was eluted in 4% ethyl acetate in hexane to obtain 5.6. (0.1 g,Yield: 11.34%). MS(ES): m/z 486.16 [M+H]⁺.

Synthesis of Compound 5.7

To a degassed solution of Core A (0.8 g, 1.25 mmol, 1.0 eq) and compound5.6 (0.668 g, 1.37 mmol, 1.1 eq) in toluene (40 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.144 g, 0.12 mmol, 0.1 eq) and thereaction mixture was heated at 100° C. for 1 h under N₂ atmosphere.Reaction mixture was cooled to room temperature and purified by columnchromatography using 5.0% ethyl acetate in hexane as eluant to obtainpure 5.7. (0.320 g, Yield: 51.85%). MS(ES): m/z 566.21 [M+H]⁺.

Synthesis of Compound 5.8

The compound was synthesized from compound 5.7 using General Procedure Bto obtain 5.8. (0.1 g, 57.23%), MS (ES): m/z 386.11 [M+H]⁺.

Synthesis of Compound 5.9

The compound was synthesized from compound 5.8 using General Procedure Cto obtain 5.9. (0.085 g, 72.24%), MS (ES): m/z 454.14 [M+H]⁺.

Synthesis of Compound I-5

The compound was synthesized from compound 5.9 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-5 (0.027 g, 31.83%), MS (ES): m/z 453.30 [M+H]⁺ LCMS purity: 100%,HPLC purity: 96.44%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.05 (s, 1H), 10.90 (s,1H), 8.35-8.33 (m, 2H), 7.84-7.82 (m, 1H), 7.66-7.64 (m, 1H), 7.59-7.56(m, 2H), 7.06 (bs, 1H), 3.14 (s, 3H), 2.83-2.82 (d, J=4.4 Hz, 3H), 2.04(bs, 1H), 1.60 (s, 2H), 0.96 (bs, 3H), 0.83-0.81 (m, 3H).

Example 6:7-(cyclopropanecarboxamido)-N-(methyl-d₃)-2-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-6)

Synthesis of Compound I-6

The compound was synthesized from compound 2.6 and methyl-d₃-amine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-6 (0.025 g, 31.10%), MS (ES): m/z 419.45 [M+H]⁺ LCMS purity: 100%,HPLC purity: 99.74%, ¹H NMR (DMSO-d₆, 400 MHz): 11.92 (s, 1H), 11.15 (s,1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.32 (s, 1H), 8.06-8.05(d, J=7.6 Hz, 1H), 7.92-7.90 (d, J=7.6 Hz, 1H), 7.67-7.63 (t, J=7.6 Hz,1H), 7.41 (s, 1H), 3.98 (s, 3H), 3.44-3.41 (m, 1H), 1.01-0.94 (m, 4H).

Example 7:7-(cyclopropanecarboxamido)-N-methyl-2-(3-(3-methyl-1H-pyrazol-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-7)

Synthesis of Compound 7.2

To a solution of compound 7.1 (3.0 g, 16.04 mmol, 1.0 eq) andbut-3-yn-2-one (1.0 g, 16.04 mmol, 1.0 eq) in methanol (30 mL) was addedhydrochloric acid (4.0M in water, 0.4 mL, 16.04 mmol, 1.0 eq). Thereaction mixture was heated in microwave for 15 min at 120° C. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to obtain residue. To this added water and was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by combi flash using 7%ethyl acetate in hexane as eluant to obtain pure 7.2. (1.3 g, Yield:34.18%). MS (ES): m/z 237.99 [M+H]⁺.

Synthesis of Compound 7.3

The compound was synthesized from compound 7.2 using General Procedure Fto obtain 7.3. (1.0 g, 64.18%). MS(ES): m/z 285.17 [M+H]⁺.

Synthesis of Compound 7.4

The compound was synthesized from Core A and compound 7.3 using GeneralProcedure A to obtain 7.4. (0.160 g, Yield: 76.37%), MS (ES): m/z 668.23[M+H]⁺.

Synthesis of Compound 7.5

The compound was synthesized from compound 7.4 using General Procedure Bto obtain 7.5. (0.070 g, Yield: 84.10%), MS (ES): m/z 348.14 [M+H]⁺.

Synthesis of Compound 7.6

The compound was synthesized from compound 7.5 using General Procedure Cto obtain 7.6. (0.050 g, 59.72%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound I-7

The compound was synthesized from compound 7.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-7 (0.020 g, 40.09%), MS (ES): m/z 415.27 [M+H]⁺ LCMS purity: 96.18%,HPLC purity: 95.44%, ¹H NMR (DMSO-d₆, 400 MHz): 11.79 (s, 1H), 11.11 (s,1H), 8.56 (s, 1H), 8.39 (bs, 1H), 8.31 (s, 2H), 7.87-7.85 (d, J=8 Hz,1H), 7.71-7.70 (d, J=7.2 Hz, 1H), 7.65-7.61 (t, J=8 Hz, 1H), 7.48 (bs,1H), 6.40 (s, 1H), 2.86-2.85 (d, J=4.4 Hz, 3H), 2.32 (s, 3H), 1.23 (bs,1H), 1.00-0.93 (m, 4H).

Example 8:2-(3-(2H-1,2,3-triazol-2-yl)phenyl)-7-(cyclopropanecarboxamido)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-8)

Synthesis of Compound 8.2

To a solution of 1,3-dibromobenzene (2.0 g, 8.47 mmol, 1.0 eq) indimethylformamide (20 mL) was added compound 8.1 (0.701 g, 10.16 mmol,1.2 eq), copper (I) iodide (0.161 g, 0.84 mmol, 0.1 eq),tris(acetylacetonato)iron(III) (0.896 g, 2.54 mmol, 0.3 eq) and cesiumcarbonate (5.5 g, 16.94 mmol, 2.0 eq). The reaction mixture was heatedat 120° C. for 16 h under N₂ atmosphere. After completion of reaction,reaction mixture was concentrated under reduced pressure to obtaincrude. This was further purified by combi flash using 15% ethyl acetatein hexane as eluant to obtain pure 8.2. (0.450 g, Yield: 23.69%). MS(ES): m/z 224.97 [M+H]⁺.

Synthesis of Compound 8.3

Argon was purged for 15 min through a stirring solution of 8.2 (0.450 g,2.00 mmol, 1.0 eq) and potassium carbonate (0.828 g, 6.00 mmol, 3.0 eq)in 1,4-dioxane (16 mL). Then bis(pinacolato)diboron (0.609 g, 2.4 mmol,1.2 eq) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (0.146 g, 0.2 mmol, 0.1 eq) were added to it and furtherpurging done for 10 min. Reaction was allowed to stir at 110° C. for 5h. After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain 8.3. (0.350 g, 64.28%).MS(ES): m/z 272.15 [M+H]⁺.

Synthesis of Compound 8.4

The compound was synthesized from Core A and compound 8.3 using GeneralProcedure A to obtain 8.4. (0.220 g, Yield: 71.40%), MS (ES): m/z 655.21[M+H]⁺.

Synthesis of Compound 8.5

The compound was synthesized from compound 8.4 using General Procedure Bto obtain 8.5. (0.105 g, Yield: 93.47%), MS (ES): m/z 335.12 [M+H]⁺.

Synthesis of Compound 8.6

The compound was synthesized from compound 8.5 using General Procedure Cto obtain 8.6. (0.1 g, Yield: 79.13%), MS (ES): m/z 403.15 [M+H]⁺.

Synthesis of Compound I-8

The compound was synthesized from compound 8.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-8 (0.025 g, 25.06%), MS (ES): m/z 402.55 [M+H]⁺ LCMS purity: 100%,HPLC purity: 98.21%, ¹H NMR (DMSO-d₆, 400 MHz): 11.82 (s, 1H), 11.12 (s,1H), 9.03 (s, 1H), 8.45 (s, 1H), 8.39-8.38 (d, J=4.4 Hz, 1H), 8.31 (s,1H), 8.05 (s, 1H), 7.98-7.94 (m, 2H), 7.79-7.75 (t, J7.6 Hz, 1H), 7.56(s, 1H), 2.86-2.85 (d, J=4.4 Hz, 3H), 2.24 (bs, 1H), 1.00 (bs, 2H),0.95-0.93 (m, 2H).

Example 9:7-(cyclopropanecarboxamido)-2-(4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-2-methoxyphenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-9)

Synthesis of Compound 9.2

To a solution of 9.1 (3.0 g, 12.24 mmol, 1.0 eq), in methanol (25 mL)was added sodium hydroxide (2.4 g, 61.2 mmol, 5.0 eq). The reactionmixture was stirred at 60° C. for 1 h. After completion of reaction,reaction mixture was concentrated under reduced pressure to obtainresidue. To this added water and acidified with 1N hydrochloric acid toadjust pH-6 at 10° C. Product was extracted with dichloromethane.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography andcompound was eluted in 2.1% methanol in dichloromethane to obtain pure9.2. (2.4 g, 84.86%). MS(ES): m/z 231.96 [M+H]⁺.

Synthesis of Compound 9.3

To the solution of compound 9.2 (2.4 g, 10.38 mmol, 1.0 eq) indichloromethane (25 mL) was added catalytic dimethylformamide (1 mL) andoxalyl chloride (1.3 mL, 15.57 mmol, 1.5 eq) was added dropwise at 0° C.The reaction mixture was stirred at 0° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain crude material. To this added tetrahydrofuran (10 mL) followed bytriethylamine (3.1 g, 31.14 mmol, 3.0 eq) and2-amino-2-methyl-1-propanol (1.8 g, 20.76 mmol, 2.0 eq) at 0° C. Thereaction mixture was stirred at room temperature for 2 h, transferredinto ice cold water and product was extracted with ethyl acetate.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography elutingwith 2.5% methanol in dichloromethane to obtain 9.3. (1.6 g, Yield:50.97%). MS (ES): m/z 302.03 [M+H]⁺.

Synthesis of Compound 9.4

To a solution of 9.3 (1.6 g, 5.29 mmol, 1.0 eq) in tetrahydrofuran (20mL) was added Burgess Reagent (2.5 g, 10.58 mmol, 2.0 eq) at 0° C. Thereaction was stirred at 0° C. for 4 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by combiflash using 3% methanol in dichloromethane as eluant to obtain pure 9.4.(0.7 g, 46.52%). MS(ES): m/z 285.02 [M+H]⁺.

Synthesis of Compound 9.5

The compound was synthesized from compound 9.4 using General Procedure Fto obtain 9.5. (0.5 g, 61.28%). MS(ES): m/z 332.20 [M+H]⁺.

Synthesis of Compound 9.6

The compound was synthesized from Core A and compound 9.5 using GeneralProcedure A to obtain 9.6. (0.140 g, Yield: 49.94%), MS (ES): m/z 715.25[M+H]⁺.

Synthesis of Compound 9.7

The compound was synthesized from compound 9.6 using General Procedure Bto obtain 9.7. (0.075 g, Yield: 97.09%), MS (ES): m/z 395.17 [M+H]⁺.

Synthesis of Compound 9.8

The compound was synthesized from compound 9.7 using General Procedure Cto obtain 9.8. (0.070 g, 74.62%), MS (ES): m/z 463.19 [M+H]⁺.

Synthesis of Compound I-9

The compound was synthesized from compound 9.8 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-9 (0.028 g, 40.09%), MS (ES): m/z 462.45 [M+H]⁺ LCMS purity: 95.00%,HPLC purity: 95.13%, ¹H NMR (DMSO-d₆, 400 MHz): 12.59 (s, 1H), 11.35 (s,1H), 8.34 (bs, 1H), 8.29 (s, 1H), 8.12-8.10 (d, J=8.4 Hz, 1H), 7.59-7.58(d, J=6.4 Hz, 2H), 7.53 (s, 1H), 4.17 (s, 2H), 4.07 (s, 2H), 2.87-2.85(d, J=4.4 Hz, 1H), 2.52 (bs, 3H), 2.26 (bs, 1H), 1.33 (s, 6H), 1.02 (bs,2H), 0.99-0.97 (d, J=7.6 Hz, 2H).

Example 10:7-(cyclopropanecarboxamido)-N-methyl-2-(4-(2-methylthiazol-4-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-10)

Synthesis of Compound 10.2

To a solution of compound 10.1 (2.0 g, 9.90 mmol, 1.0 eq), indichloromethane (40 mL) was added N,O-dimethylhydroxylaminehydrochloride (1.4 g, 14.85 mmol, 1.5 eq),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.6 g, 10.89 mmol, 1.1eq), hydroxybenzotriazole (1.4 g, 10.89 mmol, 1.1 eq) and triethylamine(3.9 g, 39.6 mmol, 4.0 eq) at 0° C. The reaction mixture was stirred atroom temperature for 16 h. After completion of reaction, reactionmixture was transferred into water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatography andthe compound was eluted in 40% ethyl acetate in hexane to obtain 10.2.(1.8 g, 74.18%). MS(ES): m/z 244.9 [M+H]⁺.

Synthesis of Compound 10.3

To a solution of compound 10.2 (1.8 g, 7.37 mmol, 1.0 eq), intetrahydrofuran (35 mL) was added methylmagnesium bromide solution (3Min hexane, 3.68 mL, 11.05 mmol, 1.5 eq) dropwise at 0° C. The reactionmixture was stirred at room temperature for 1 h. After completion ofreaction, 1N hydrochloric acid was added to the reaction mixture andextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 15% ethyl acetate inhexane to obtain 10.3. (1.35 g, 91.89%). MS(ES): m/z 199.97 [M+H]⁺.

Synthesis of Compound 10.4

To compound 10.3 (1.35 g, 6.75 mmol, 1.0 eq) added hydrogen bromidesolution 30% in acetic acid (10 mL) followed by bromine (0.34 mL, 6.75mmol, 1.0 eq) dropwise at 15° C. The reaction mixture was stirred at 60°C. for 2 h. After completion of reaction, reaction mixture was cooled to20° C., diluted with diethyl ether and stirred for 30 min. Theprecipitated product was filtered, washed with diethyl ether and driedunder vacuum to obtain pure 10.4. (1.1 g, 58.43%). MS(ES): m/z 278.87[M+H]⁺.

Synthesis of Compound 10.5

To a solution of compound 10.4 (1.1 g, 3.95 mmol, 1.0 eq), in ethanol(30 mL) was added ethanethioamide (0.296 g, 3.95 mmol, 1.0 eq). Thereaction mixture was refluxed for 1 h. After completion of reaction,reaction mixture was cooled to obtain the precipitate which was filteredand dried to obtain 10.5. (0.650 g, 64.60%). MS(ES): m/z 254.95 [M+H]⁺.

Synthesis of Compound 10.6

The compound was synthesized from Core C and compound 10.5 using GeneralProcedure E to obtain 10.6. (0.120 g, 15.57%). MS (ES): m/z 686.19[M+H]⁺.

Synthesis of Compound 10.7

The compound was synthesized from compound 10.6 using General ProcedureB to obtain 10.7. (0.063 g, 98.53%), MS (ES): m/z 366.10 [M+H]⁺.

Synthesis of Compound 10.8

The compound was synthesized from compound 10.7 using General ProcedureC to obtain 10.8. (0.060 g, 72.25%), MS (ES): m/z 434.12 [M+H]⁺.

Synthesis of Compound I-10

The compound was synthesized from compound 10.8 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-10 (0.016 g, 26.73%), MS (ES): m/z 433.32 [M+H]⁺ LCMS purity: 100%,HPLC purity: 97.41%, ¹H NMR (DMSO-d₆, 400 MHz): 12.14 (s, 1H), 11.33 (s,1H), 8.76-8.74 (d, J=5.2 Hz, 1H), 8.63 (bs, 1H), 8.60 (s, 1H), 8.44-8.43(d, J=4.4 Hz, 1H), 8.31 (s, 1H), 7.94-7.93 (d, J=5.2 Hz, 1H), 7.77-7.77(d, J=2 Hz, 1H), 2.88-2.87 (d, J=4.4 Hz, 3H), 2.80 (s, 3H), 1.35 (bs,1H), 1.24 (m, 4H).

Example 11:7-(cyclopropanecarboxamido)-2-(3-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-11)

Synthesis of Compound 11.1

To the solution of 3-bromobenzoic acid (3.0 g, 14.92 mmol, 1.0 eq) indichloromethane (30 mL) was added catalytic dimethylformamide (1 mL) andoxalyl chloride (1.9 mL, 22.38 mmol, 1.5 eq) dropwise at 0° C. Thereaction mixture was stirred at 0° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain crude material. To this added tetrahydrofuran (15 mL) followed bytriethylamine (4.5 g, 44.76 mmol, 3.0 eq) and2-amino-2-methylpropan-1-ol (2.6 g, 29.84 mmol, 2.0 eq) at 0° C. Thereaction mixture was stirred at room temperature for 2 h, thentransferred to ice cold water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatographyeluting with 2.5% methanol in dichloromethane to obtain 11.1. (2.8 g,Yield: 68.94%). MS (ES): m/z 273.02 [M+H]⁺.

Synthesis of Compound 11.2

To a solution of 11.1 (2.8 g, 10.29 mmol, 1.0 eq), in toluene (40 mL)was added phosphorus pentasulfide (1.4 g, 5.14 mmol, 0.5 eq). Thereaction mixture was stirred at 120° C. for 3 h. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 3% methanol indichloromethane to obtain 11.2. (1.0 g, 35.97%). MS (ES): m/z 270.99[M+H]⁺.

Synthesis of Compound 11.3

The compound was synthesized from compound 11.2 using General ProcedureF to obtain 11.3. (0.650 g, 55.36%). MS (ES): m/z 318.17 [M+H]⁺.

Synthesis of Compound 11.4

The compound was synthesized from Core A and compound 11.3 using GeneralProcedure A to obtain 11.4. (0.190 g, Yield: 44.39%), MS (ES): m/z546.22 [M+H]⁺.

Synthesis of Compound 11.5

The compound was synthesized from compound 11.4 using General ProcedureB to obtain 11.5. (0.090 g, Yield: 67.94%), MS (ES): m/z 381.13 [M+H]⁺.

Synthesis of Compound 11.6

The compound was synthesized from compound 11.5 using General ProcedureC to obtain 11.6. (0.070 g, Yield: 65.97%), MS (ES): m/z 449.16 [M+H]⁺.

Synthesis of Compound I-11

The compound was synthesized from compound 11.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-11 (0.025 g, 35.79%), MS (ES): m/z 448.27 [M+H]⁺ LCMS purity: 99.55%,HPLC purity: 95.11%, ¹H NMR (DMSO-d₆, 400 MHz): 11.92 (s, 1H), 11.14 (s,1H), 8.40 (bs, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 8.03-8.01 (d, J=8 Hz,1H), 7.79-7.77 (d, J=7.6 Hz, 1H), 7.67-7.64 (t, J=7.6 Hz, 1H), 7.40 (s,1H), 2.87-2.85 (d, J=4.4 Hz, 3H), 2.51 (s, 2H), 2.27 (bs, 1H), 1.44 (s,6H), 0.99 (bs, 2H), 0.95-0.93 (d, J=7.6 Hz, 2H).

Example 12:7-(cyclopropanecarboxamido)-2-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-12)

Synthesis of Compound 12.1

To a solution of compound 2.4 (0.190 g, 0.28 mmol, 1.0 eq), in methanol(3 mL) was added sodium hydroxide (0.056 g, 1.4 mmol, 5.0 eq). Thereaction mixture was stirred at 70° C. for 24 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue. To this added water and acidified with 1N hydrochloricacid to adjust pH-6 at 10° C. Product was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 12.1. (0.110 g, 59.14%). MS(ES): m/z655.21 [M+H]⁺.

Synthesis of Compound 12.2

To a solution of compound 12.1 (0.080 g, 0.12 mmol, 1.0 eq), inN,N-dimethylformamide (2 mL) was added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.091 g, 0.24 mmol, 2.0 eq) and stirred atroom temperature for 15 min. To this added diisopropylethylamine (0.046g, 0.36 mmol, 3.0 eq) followed by addition of 30% aqueous ammonia (0.033mL, 0.12 mmol, 1.3 eq). The reaction mixture was stirred at roomtemperature for 5 min. After completion of reaction, reaction mixturewas transferred into water and product was extracted with ethyl acetate.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography and thecompound was eluted in 40% ethyl acetate in hexane to obtain 12.2.(0.070 g, 87.63%). MS(ES): m/z 654.22 [M+H]⁺.

Synthesis of Compound 12.3

The compound was synthesized from compound 12.2 using General ProcedureB to obtain 12.3. (0.035 g, 98.06%), MS (ES): m/z 334.14 [M+H]⁺.

Synthesis of Compound I-12

The compound was synthesized from compound 12.3 using General ProcedureC to obtain I-12 (0.030 g, 62.28%), MS (ES): m/z 402.12 [M+H]⁺ LCMSpurity: 99.30%, HPLC purity: 97.73%, ¹H NMR (DMSO-d₆, 400 MHz): 11.90(s, 1H), 11.13 (s, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 8.41 (s, 1H),8.07-8.05 (d, J=7.6 Hz, 1H), 7.93-7.91 (d, J=7.2 Hz, 3H), 7.67-7.63 (t,J=7.6 Hz, 2H), 7.47 (bs, 2H), 7.42 (s, 1H), 2.29 (bs, 1H), 1.01 (bs,2H), 0.96-0.95 (d, J=7.6 Hz, 2H).

Example 13:7-(cyclopropanecarboxamido)-N-methyl-2-(4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-13)

Synthesis of compound 13.2

To a solution of compound 13.1 (2.8 g, 12.44 mmol, 1.0 eq) indimethylformamide (30 mL), was added sodium hydride (0.597 g, 24.88mmol, 2 eq) at 0° C. and stirred for 20 min. Methyl iodide (1.9 g, 13.68mmol, 1.1 eq) was added and reaction mixture was stirred at roomtemperature for 2 h. After completion of reaction, reaction mixture wastransferred into ice, stirred and extracted with diethyl ether. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bydistillation to obtain pure 13.2. (1.0 g, Yield: 33.62%). MS (ES): m/z238.99 [M+H]⁺.

Synthesis of Compound 13.3

The compound was synthesized from Core C and compound 13.2 using GeneralProcedure E to obtain 13.3. (0.130 g, 15.54%). MS (ES): m/z 670.22[M+H]⁺.

Synthesis of Compound 13.4

The compound was synthesized from compound 13.3 using General ProcedureB to obtain 13.4. (0.067 g, Yield: 98.81%), MS (ES): m/z 350.13 [M+H]⁺.

Synthesis of Compound 13.5

The compound was synthesized from compound 13.4 using General ProcedureC to obtain 13.5. (0.045 g, 50.22%), MS (ES): m/z 418.16 [M+H]⁺.

Synthesis of Compound I-13

The compound was synthesized from compound 13.5 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-13 (0.027 g, 60.14%), MS (ES): m/z 417.47 [M+H]⁺ LCMS purity: 98.74%,HPLC purity: 95.00%, ¹H NMR (DMSO-d₆, 400 MHz): 12.21 (s, 1H), 11.34 (s,1H), 8.81 (bs, 1H), 8.54 (s, 1H), 8.38 (bs, 1H), 7.94 (bs, 1H), 7.69(bs, 1H), 7.08 (bs, 1H), 6.84 (bs, 1H), 4.02 (s, 3H), 2.88 (s, 3H), 1.56(bs, 1H), 1.01-0.97 (m, 4H).

Example 14:7-(cyclopropanecarboxamido)-N-methyl-2-(4-(thiazol-2-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-14)

Synthesis of Compound 14.2

Argon was purged for 15 min through a stirred solution of2-bromo-4-iodopyridine (3.0 g, 10.60 mmol, 1.0 eq), compound 14.1 (5.1g, 13.78 mmol, 1.3 eq) and copper(I) iodide (0.201 g, 1.06 mmol, 0.1 eq)in 1,4-dioxane (50 mL). Bis(triphenylphosphine)palladium(II) dichloride(0.743 g, 1.06 mmol, 0.1 eq) was added to it and further purging donefor 10 min. Reaction was allowed to stir at 110° C. for 1 h. Aftercompletion of reaction, reaction mixture was transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain 14.2. (0.7 g, 27.47%). MS (ES): m/z241.93 [M+H]⁺.

Synthesis of Compound 14.3

The compound was synthesized from Core C and compound 14.2 using GeneralProcedure E to obtain 14.3. (0.130 g, 15.49%). MS (ES): m/z 672.17[M+H]⁺.

Synthesis of Compound 14.4

The compound was synthesized from compound 14.3 using General ProcedureB to obtain 14.4. (0.067 g, Yield: 98.53%), MS (ES): m/z 352.08 [M+H]⁺.

Synthesis of Compound 14.5

The compound was synthesized from compound 14.4 using General ProcedureC to obtain 14.5. (0.058 g, 63.10%), MS (ES): m/z 420.11 [M+H]⁺.

Synthesis of Compound I-14

The compound was synthesized from compound 14.5 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-14 (0.023 g, 39.75%), MS (ES): m/z 419.80 [M+H]⁺ LCMS purity: 97.05%,HPLC purity: 98.91%, ¹H NMR (DMSO-d₆, 400 MHz): 12.20 (s, 1H), 11.35 (s,1H), 8.84-8.83 (d, J=5.2 Hz, 1H), 8.57 (bs, 1H), 8.41-8.40 (d, J=4.4 Hz,1H), 8.14-8.13 (d, J=3.2 Hz, 1H), 7.96-7.95 (m, 1H), 7.81 (d, J=2 Hz,1H), 7.08 (bs, 1H), 6.84 (bs, 1H), 2.89-2.88 (d, J=4.4 Hz, 3H), 1.56(bs, 1H), 1.01-0.96 (m, 4H).

Example 15:7-(cyclopropanecarboxamido)-N-methyl-2-(4-(oxazol-2-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-15)

Synthesis of Compound 15.3

To a solution of 15.1 (6.0 g, 29.70 mmol, 1.0 eq) and 15.2 (3.12 g,29.70 mmol, 1.0 eq) in tetrahydrofuran (70 mL), was added triethylamine(5.0 g, 50.49 mmol, 1.7 eq) and carbonyldiimidazole (5.7 g, 35.64 mmol,1.2 eq). Reaction mixture was stirred at 100° C. for 2 h. Aftercompletion of reaction, reaction mixture was transferred into ice,stirred and extracted with diethyl ether. Organic layer was combined,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by distillation toobtain pure 15.3. (4.6 g, Yield: 53.57%). MS (ES): m/z 290.01 [M+H]⁺.

Synthesis of Compound 15.4

To the compound 15.3 (0.045 g, 0.10 mmol, 1.0 eq) was added Eaton'sReagent (7.7 wt % phosphorus pentoxide solution in methanesulfonic acid)(0.5 mL). Then reaction mixture was stirred at 80° C. for 2 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain 15.4. (0.640 g, Yield:17.87%). MS (ES): m/z 225.96 [M+H]⁺.

Synthesis of Compound 15.5

The compound was synthesized from Core C and compound 15.4 using GeneralProcedure E to obtain 15.5. (0.150 g, 18.32%). MS (ES): m/z 656.19[M+H]⁺.

Synthesis of Compound 15.6

The compound was synthesized from compound 15.5 using General ProcedureB to obtain 15.6. (0.076 g, Yield: 99.08%), MS (ES): m/z 336.11 [M+H]⁺.

Synthesis of Compound 15.7

The compound was synthesized from compound 15.6 using General ProcedureC to obtain 15.7. (0.046 g, 68.46%), MS (ES): m/z 404.13 [M+H]⁺.

Synthesis of Compound I-15

The compound was synthesized from compound 15.7 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-15 (0.025 g, 35.80%), MS (ES): m/z 403.42 [M+H]⁺ LCMS purity: 97.14%,HPLC purity: 95.00%, ¹H NMR (DMSO-d₆, 400 MHz): 12.08 (s, 1H), 10.99 (s,1H), 8.88-8.87 (d, J=5.2 Hz, 1H), 8.51 (s, 1H), 8.34-8.33 (d, J=4.4 Hz,2H), 8.06 (bs, 1H), 7.91-7.90 (d, J=4.2 Hz, 1H), 7.73 (s, 1H), 7.53 (s,1H), 2.92-2.91 (d, J=4.4 Hz, 3H), 1.32-1.29 (m, 1H), 1.04-0.95 (m, 4H).

Example 16:7-(cyclopropanecarboxamido)-N-(methyl-d3)-2-(4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-16)

Synthesis of Compound I-16

The compound was synthesized from compound 13.5 and methyl-d₃-amineusing General Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-16 (0.025 g, 38.28%), MS (ES): m/z 420.80 [M+H]⁺ LCMS purity: 95.11%,HPLC purity: 97.40%, ¹H NMR (DMSO-d₆, 400 MHz): 12.01 (s, 1H), 10.92 (s,1H), 8.80-8.78 (d, J=4.8 Hz, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.33 (s,1H), 8.02 (bs, 1H), 7.93-7.91 (d, J=4.4 Hz, 1H), 7.65 (s, 1H), 4.02 (s,3H), 1.27 (bs, 1H), 1.04-0.94 (m, 4H).

Example 17:7-(cyclopropanecarboxamido)-N-methyl-2-(4-(3-methyl-1H-pyrazol-1-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-17)

Synthesis of Compound 17.1

To a solution of 2-chloro-4-iodopyridine (1.0 g, 4.18 mmol, 1.0 eq) andpotassium carbonate (1.73 g, 12.54 mmol, 3.0 eq) in toluene (15 mL) wasadded 3-methyl-1H-pyrazole (1.0 g, 12.54 mmol, 3.0 eq),trans-1,2-diaminocyclohexane (0.190 g, 1.67 mmol, 0.4 eq) and copper(I)iodide (0.159 g, 0.83 mmol, 0.2 eq). The reaction mixture was heated at110° C. for 16 h. After completion of reaction, reaction mixture wastransferred into ice cold water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatographyeluting with 20% ethyl acetate in hexane to obtain 17.1. (0.320 g,39.57%), MS (ES): m/z 194.04 [M+H]⁺.

Synthesis of Compound 17.2

To a solution of compound 17.1 (0.320 g, 1.65 mmol, 1.0 eq) inacetonitrile (5 mL) was added sodium iodide (1.2 g, 8.25 mmol, 5 eq) andacetyl chloride (0.194 g, 2.47 mmol, 1.5 eq). The reaction mixture washeated at 70° C. for 16 h. After completion of reaction, reactionmixture was transferred into ice cold water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography eluting with 20% ethyl acetate in hexane to obtain 17.2.(0.3 g, 63.68%), MS (ES): m/z 285.97 [M+H]⁺.

Synthesis of Compound 17.3

The compound was synthesized from Core C and compound 17.2 using GeneralProcedure E to obtain 17.3. (0.110 g, 13.17%). MS (ES): m/z 669.22[M+H]⁺.

Synthesis of Compound 17.4

The compound was synthesized from compound 17.3 using General ProcedureB to obtain 17.4. (0.057 g, Yield: 99.48%), MS (ES): m/z 349.14 [M+H]⁺.

Synthesis of Compound 17.5

The compound was synthesized from compound 17.4 using General ProcedureC to obtain 17.5. (0.056 g, 71.70%), MS (ES): m/z 417.16 [M+H]⁺.

Synthesis of Compound I-17

The compound was synthesized from compound 17.5 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-17 (0.025 g, 38.28%), MS (ES): m/z 416.32 [M+H]⁺ LCMS purity: 97.43%,HPLC purity: 98.38%, ¹H NMR (DMSO-d₆, 400 MHz): 11.97 (s, 1H), 10.92 (s,1H), 8.69 (s, 2H), 8.43 (s, 1H), 8.30 (s, 1H), 8.08 (s, 1H), 7.81 (s,1H), 7.75 (s, 1H), 6.47 (bs, 1H), 2.91-2.90 (d, J=4.8 Hz, 3H), 2.35 (s,3H), 1.27 (bs, 1H), 1.03-0.94 (m, 4H).

Example 18:2-(3-(4H-1,2,4-triazol-4-yl)phenyl)-7-(cyclopropanecarboxamido)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-18)

Synthesis of Compound 18.2

To a suspension of 3-bromoaniline (2.0 g, 11.62 mmol, 1.0 eq) in toluene(30 mL) was added compound 18.1 (3.3 g, 23.24 mmol, 2.0 eq) and reactionmixture was heated at 120° C. for 24 h. After completion of reaction,reaction mixture was concentrated under reduced pressure to obtainresidue which was dissolved in saturated sodium bicarbonate solution andwashed with hexane. Aqueous layer separated and acidified with 1Nhydrochloric acid to pH-5-6 and extracted with ethyl acetate. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain solid which was triturated with hexane toobtain pure 18.2. (0.650 g, Yield: 24.95%). MS (ES): m/z 224.97 [M+H]⁺.

Synthesis of Compound 18.3

To a solution of 18.2 (0.650 g, 2.90 mmol, 1.0 eq) in 1,4-dioxane (20mL) was added bis(pinacolato)diboron (0.883 g, 3.48 mmol, 1.2 eq) andpotassium acetate (0.568 g, 5.8 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 min. under argon atmosphere, then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.211 g,0.29 mmol, 0.1 eq) was added, again degassed for 5 min. The reaction wasstirred at 90° C. for 4 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 3% methanol in dichloromethane as eluantto obtain pure 18.3. (0.4 g, Yield:50.86%). MS(ES): m/z 272.15 [M+H]⁺.

Synthesis of Compound 18.4

The compound was synthesized from Core A and compound 18.3 using GeneralProcedure A to obtain 18.4. (0.210 g, Yield: 40.89%), MS (ES): m/z655.21 [M+H]⁺.

Synthesis of Compound 18.5

The compound was synthesized from compound 18.4 using General ProcedureB to obtain 18.5. (0.106 g, Yield: 98.85%), MS (ES): m/z 335.12 [M+H]⁺.

Synthesis of Compound 18.6

The compound was synthesized from compound 18.5 using General ProcedureC to obtain 18.6. (0.070 g, Yield:67.39%), MS (ES): m/z 403.13 [M+H]⁺.

Synthesis of Compound I-18

The compound was synthesized from compound 18.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-18 (0.025 g, 34.55%), MS (ES): m/z 402.79 [M+H]⁺ LCMS purity: 100%,HPLC purity: 98.95%, ¹H NMR (DMSO-d₆, 400 MHz): 11.74 (s, 1H), 11.15 (s,1H), 9.30 (s, 2H), 8.41-8.40 (d, J=4.8 Hz, 1H), 8.31 (s, 2H), 7.89-7.88(d, J=7.6 Hz, 1H), 7.80-7.72 (m, 2H), 7.60 (bs, 1H), 2.87-2.86 (d, J=4.4Hz, 3H), 1.31 (bs, 1H), 1.01-0.94 (m, 4H).

Example 19:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-19)

Synthesis of Compound 19.1

To a solution of 1-fluoro-2-iodobenzene (2.0 g, 9.00 mmol, 1.0 eq) intetrahydrofuran (20 mL) was added lithium diisopropylamide (2M) (9.0 mL,18.0 mmol, 2.0 eq) at −78° C. The reaction mixture was stirred at −78°C. for 1 h. Then a solution of iodine (2.2 g, 18.0 mmol, 2.0 eq) intetrahydrofuran (12 mL) was added to reaction mixture and stirred for 2h at same temperature. After completion of reaction, reaction mixturewas transferred to ice cold water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatographyeluting with 7% ethyl acetate in hexane to obtain 19.1. (1.8 g, Yield:57.43%). MS (ES): m/z 348.83 [M+H]⁺.

Synthesis of Compound 19.3

Argon was purged for 15 min through a stirred mixture of compound 19.1(1.6 g, 4.61 mmol, 1.0 eq), compound 19.2 (1.2 g, 5.99 mmol, 1.3 eq) andtripotassium phosphate (2.4 g, 11.52 mmol, 2.5 eq) in 1,4-dioxane (60mL). [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride(0.336 mg, 046 mmol, 0.1 eq) was added to it and further purging donefor 10 min. Reaction was stirred at 95° C. for 6 h. After completion ofreaction, reaction mixture was poured over water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain 19.3. (0.650 g, Yield: 46.79%). MS (ES): m/z 302.97[M+H]⁺.

Synthesis of Compound 19.4

The compound was synthesized from compound 19.3 using General ProcedureF to obtain 19.4. (0.4 g, Yield: 61.53%). MS(ES): m/z 303.16 [M+H]⁺.

Synthesis of Compound 19.5

The compound was synthesized from Core A and compound 19.4 using GeneralProcedure A to obtain 19.5. (0.260 g, Yield: 53.71%), MS (ES): m/z686.22 [M+H]⁺.

Synthesis of Compound 19.6

The compound was synthesized from compound 19.5 using General ProcedureB to obtain 19.6. (0.120 g, Yield: 86.63%), MS (ES): m/z 366.13 [M+H]⁺.

Synthesis of Compound 19.7

The compound was synthesized from compound 19.6 using General ProcedureC to obtain 19.7. (0.110 g, Yield: 77.27%), MS (ES): m/z 434.16 [M+H]⁺.

Synthesis of Compound I-19

The compound was synthesized from compound 19.7 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-19 (0.025 g, Yield: 22.78%), MS (ES): m/z 433.51 [M+H]⁺ LCMS purity:98.70%, HPLC purity: 97.71%, ¹H NMR (DMSO-d₆, 400 MHz): 12.18 (s, 1H),11.47 (s, 1H), 8.57 (s, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.84-7.80 (m,1H), 7.51 (s, 1H), 7.43-7.39 (t, J=7.6 Hz, 1H), 7.10 (bs, 1H), 6.82 (bs,1H), 3.95 (bs, 3H), 1.56 (bs, 3H), 1.24 (bs, 1H), 1.03-0.97 (m, 4H).

Example 20:7-(cyclopropanecarboxamido)-2-(2-cyclopropyl-2H-indazol-6-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-20)

Synthesis of Compound 20.1

To 4-bromo-2-fluorobenzaldehyde (3.0 g, 14.77 mmol, 1.0 eq) was addedhydrazine hydrate (0.850 g, 26.58 mmol, 1.8 eq). The reaction mixturewas stirred at room temperature for 20 h. After completion of reaction,reaction mixture was transferred into ice cold water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtain20.1. (1.9 g, 65.25%), MS (ES): m/z 196.97 [M+H]⁺.

Synthesis of Compound 20.2

To a solution of compound 20.1 (1 g, 5.12 mmol, 1.0 eq) in1,2-dichloroethane (10 mL) was added cyclopropylboronic acid (0.528 g,6.14 mmol, 1.8 eq), sodium carbonate (1.3 g, 12.8 mmol, 2.5 eq), cupricacetate (1.3 g, 7.68 mmol, 1.5 eq), and bipyridine (1.5 g, 10.24 mmol,2.0 eq). The reaction mixture was stirred at room temperature for 6 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography eluting with 2% methanol indichloromethane to obtain 20.2. (0.820 g, 68.14%), MS (ES): m/z 237.99[M+H]⁺.

Synthesis of Compound 20.3

The compound was synthesized from compound 20.2 using General ProcedureF to obtain 20.3. (0.4 g, 47.68%). MS(ES): m/z 285.17 [M+H]⁺.

Synthesis of Compound 20.4

The compound was synthesized from Core A and compound 20.3 using GeneralProcedure A to obtain 20.4. (0.210 g, 44.55%), MS (ES): m/z 668.23[M+H]⁺.

Synthesis of Compound 20.5

The compound was synthesized from compound 20.4 using General ProcedureB to obtain 20.5. (0.1 g, 91.54%), MS (ES): m/z 348.14 [M+H]⁺.

Synthesis of Compound 20.6

The compound was synthesized from compound 20.5 using General ProcedureC to obtain 20.6. (0.1 g, 83.61%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound I-20

The compound was synthesized from compound 20.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-20 (0.032 g, 32.08%), MS (ES): m/z 415.27 [M+H]⁺ LCMS purity: 95.82%,HPLC purity: 96.09%, ¹H NMR (DMSO-d₆, 400 MHz): 11.88 (s, 1H), 11.14 (s,1H), 8.38-8.37 (d, J=4.4 Hz, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 8.07 (s,1H), 7.92-7.90 (d, J=8.4 Hz, 1H), 7.63-7.61 (d, J=8.4 Hz, 1H), 7.49-7.48(d, J=2 Hz, 1H), 2.86-2.85 (d, J=4 Hz, 3H), 2.26 (bs, 1H), 1.54 (bs,1H), 1.23-1.17 (m, 4H), 1.01-0.93 (m, 4H).

Example 21:7-(cyclopropanecarboxamido)-2-(7-fluoro-1-methyl-1H-indol-6-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-21)

Synthesis of Compound 21.2

To a solution of compound 21.1 (10.0 g, 45.45 mmol, 1.0 eq) intetrahydrofuran (200 mL) was added vinyl magnesium bromide (1M in THF,136 mL, 136.35 mmol, 3.0 eq) at −78° C. The reaction mixture was stirredat −40° C. for 1 h. After completion of reaction, reaction mixture wastransferred to ice cold water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatographyeluting with 10% ethyl acetate in hexane to obtain 21.2. (1.5 g, Yield:15.42%). MS (ES): m/z 214.96 [M+H]⁺.

Synthesis of Compound 21.3

To a solution of 21.2 (1.5 g, 7.00 mmol, 1.0 eq) in dimethylformamide(15 mL), was added sodium hydride (0.336 g, 14.00 mmol, 2 eq) at 0° C.and stirred for 20 min. Methyl iodide (1.0 g, 7.7 mmol, 1.1 eq) wasadded and reaction mixture was stirred at 10° C. for 2 h. Aftercompletion of reaction, reaction mixture was transferred into ice,stirred and extracted with diethyl ether. Organic layer was combined,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by distillation toobtain pure 21.3. (1.2 g, Yield: 75.08%). MS (ES): m/z 228.97 [M+H]⁺.

Synthesis of Compound 21.4

The compound was synthesized from compound 21.3 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 21.4. (0.6g, 41.45%). MS (ES): m/z 276.15 [M+H]⁺.

Synthesis of Compound 21.5

The compound was synthesized from Core A and compound 21.4 using GeneralProcedure A to obtain 21.5. (0.190 g, 40.86%), MS (ES): m/z 659.21[M+H]⁺.

Synthesis of Compound 21.6

The compound was synthesized from compound 21.5 using General ProcedureB to obtain 21.6. (0.090 g, 92.23%), MS (ES): m/z 339.12 [M+H]⁺.

Synthesis of Compound 21.7

The compound was synthesized from compound 21.6 using General ProcedureC to obtain 21.7. (0.090 g, 83.25%), MS (ES): m/z 407.15 [M+H]⁺.

Synthesis of Compound I-21

The compound was synthesized from compound 21.7 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-21 (0.030 g, 33.41%), MS (ES): m/z 406.20 [M+H]⁺ LCMS purity: 98.45%,HPLC purity: 95.07%, ¹H NMR (DMSO-d₆, 400 MHz): 11.98 (s, 1H), 11.30 (s,1H), 8.38-8.37 (d, J=4 Hz, 1H), 7.53-7.49 (m, 2H), 7.43 (s, 1H),7.09-7.07 (d, J=8 Hz, 1H), 6.84-6.82 (d, J=7.6 Hz, 1H), 6.55 (s, 1H),4.07 (s, 3H), 2.86-2.85 (d, J=4.4 Hz, 3H), 1.56 (bs, 1H), 1.01-0.95 (m,4H).

Example 22:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-morpholinophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-22)

Synthesis of Compound 22.1

To the solution of compound 21.1 (10.0 g, 45.45 mmol, 1.0 eq) in1,4-dioxane (300 mL) was added tin(II) chloride (43.0 g, 227.25 mmol,5.0 eq). The reaction mixture was stirred at room temperature for 3 h.After completion of reaction, reaction mixture was transferred to icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography eluting with 2.5% methanol indichloromethane to obtain 22.1. (5.0 g, 57.89%). MS (ES): m/z 190.96[M+H]⁺.

Synthesis of Compound 22.3

To a cooled solution of compounds 22.1 (5.0 g, 26.31 mmol, 1.0 eq) and22.2 (7.2 g, 31.57 mmol, 1.2 eq) in n-butanol (150 mL) at 0° C. wasadded potassium carbonate (9.0 g, 65.77 mmol, 2.5 eq). The reaction wasstirred at 130° C. for 48 h. After completion of reaction, reactionmixture was transferred into water and product was extracted with ethylacetate. Organic layer was combined and dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and compound was eluted in 20%ethyl acetate in hexane to obtain pure 22.3. (0.9 g, 13.15%). MS (ES):m/z 261.00 [M+H]⁺.

Synthesis of Compound 22.4

The compound was synthesized from compound 22.3 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 22.4.(0.650 g, 61.16%). MS (ES): m/z 308.18 [M+H]⁺.

Synthesis of Compound 22.5

The compound was synthesized from Core A and compound 22.4 using GeneralProcedure A to obtain 22.5. (0.220 g, 45.12%), MS (ES): m/z 691.23[M+H]⁺.

Synthesis of Compound 22.6

The compound was synthesized from compound 22.5 using General ProcedureB to obtain 22.6. (0.115 g, 97.49%), MS (ES): m/z 371.15 [M+H]⁺.

Synthesis of Compound 22.7

The compound was synthesized from compound 22.6 using General ProcedureC to obtain 22.7. (0.110 g, 71.48%), MS (ES): m/z 439.17 [M+H]⁺.

Synthesis of Compound I-22

The compound was synthesized from compound 22.7 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-22 (0.050 g, 45.56%), MS (ES): m/z 438.42 [M+H]⁺ LCMS purity: 100%,HPLC purity: 99.42%, ¹H NMR (DMSO-d₆, 400 MHz): 11.94 (s, 1H), 11.28 (s,1H), 8.38-8.37 (d, J=4.4 Hz, 1H), 8.30 (s, 1H), 7.52-7.49 (t, J=7.2 Hz,1H), 7.41 (bs, 1H), 7.31-7.27 (t, J=8 Hz, 1H), 7.17-7.13 (t, J=7.6 Hz,1H), 3.79 (bs, 4H), 3.06 (bs, 4H), 2.84-2.83 (d, J=4.4 Hz, 3H), 2.24(bs, 1H), 0.98-0.93 (m, 4H).

Example 23:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-(oxazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-23)

Synthesis of Compound 23.1

Carbon dioxide was purged for 15 min through a stirred solution of1-bromo-2-fluorobenzene (5.0 g, 28.57 mmol, 1.0 eq) in tetrahydrofuran(70 mL) followed by addition of lithium diisopropylamide (2M) (42.8 mL,85.71 mmol, 3.0 eq) at −78° C. The reaction mixture was stirred at −78°C. for 1 h. After completion of reaction, reaction mixture wastransferred to ice cold water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatographyeluting with 7% ethyl acetate in hexane to obtain 23.1. (1.3 g, Yield:20.78%). MS (ES): m/z 218.94 [M+H]⁺.

Synthesis of Compound 23.3

To a solution of compound 23.1 (1.3 g, 5.96 mmol, 1.0 eq), intetrahydrofuran (40 mL) was added isopropyl carbonyl chloride (1.1 g,11.92 mmol, 2.0 eq) and stirred at room temperature for 15 min. To thisadded N-methylmorpholine (1.80 g, 17.88 mmol, 3.0 eq) followed byaddition of compound 23.2 (0.625 g, 5.96 mmol, 1.0 eq). The reactionmixture was stirred at room temperature for 5 min. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 40% ethyl acetate inhexane to obtain 23.3 (0.9 g, Yield: 49.53%). MS (ES): m/z 307.00[M+H]⁺.

Synthesis of Compound 23.4

To a solution of 23.3 (0.9 g, 2.94 mmol, 1.0 eq), in toluene (10 mL) wasadded phosphorus pentoxide (0.652 g, 1.47 mmol, 0.5 eq). The reactionmixture was stirred at 110° C. for 3 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 3% methanol indichloromethane to obtain 23.4. (0.6 g, Yield: 84.32%). MS (ES): m/z242.95 [M+H]⁺.

Synthesis of Compound 23.5

The compound was synthesized from compound 23.4 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 23.5.(0.450, Yield: 62.79%). MS (ES): m/z 290.13 [M+H]⁺.

Synthesis of Compound 23.6

The compound was synthesized from Core A and compound 23.5 using GeneralProcedure A to obtain 23.6. (0.210 g, Yield: 44.22%), MS (ES): m/z673.19 [M+H]⁺.

Synthesis of Compound 23.7

The compound was synthesized from compound 23.6 using General ProcedureB to obtain 23.7. (0.115 g, Yield: 87.63%), MS (ES): m/z 352.12 [M+H]⁺.

Synthesis of Compound 23.8

The compound was synthesized from compound 23.7 using General ProcedureC to obtain 23.8. (0.100 g, Yield: 86.96%), MS (ES): m/z 421.14 [M+H]⁺.

Synthesis of Compound I-23

The compound was synthesized from compound 23.8 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-23 (0.027 g, Yield: 27.06%), MS (ES): m/z 420.32 [M+H]⁺ LCMS purity:95.56%, HPLC purity: 97.22%, ¹H NMR (DMSO-d₆, 400 MHz): 12.14 (s, 1H),11.33 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.16-8.07 (m, 1H), 7.55 (s,1H), 7.09 (bs, 2H), 6.84 (bs, 2H), 2.87-2.86 (d, J=4.4 Hz, 3H), 1.56(bs, 1H), 1.01-0.95 (m, 4H).

Example 24:2-(4-(azetidine-1-carbonyl)-2-methoxyphenyl)-7-(cyclopropanecarboxamido)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-24)

Synthesis of Compound 24.2

To a solution of compound 24.1 (10.0 g, 43.29 mmol, 1.0 eq) indimethylformamide (100 mL), methyl iodide (6.7 g, 47.61 mmol, 1.1 eq)was added. The reaction mixture was degassed for 10 min under argonatmosphere followed by addition of potassium carbonate (17.9 g, 129.87mmol, 3.0 eq). The reaction mixture was heated at 100° C. for 10 h.After completion of reaction, reaction mixture was transferred to icecold water and product was extracted with ethylacetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography eluting with 5% methanol indichloromethane to obtain 24.2. (7.2 g, Yield: 67.88%). MS (ES): m/z244.98 [M+H]⁺.

Synthesis of Compound 24.3

To a solution of compound 24.2 (7.2 g, 29.38 mmol, 1.0 eq), intetrahydrofuran:methanol:water (80 mL, 2:2:1) was added lithiumhydroxide (7.0 g, 293.8 mmol, 10 eq). The reaction was stirred at 60° C.for 16 h. After completion of reaction, reaction mixture wasconcentrated under reduced pressure to obtain residue. To this addedwater and acidified with 1N hydrochloric acid to adjust pH-6-6.5 at 10°C. Product was extracted with dichloromethane. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and compound was eluted in2.1% methanol in dichloromethane to obtain pure 24.3. (5.0 g, Yield:73.66%). MS (ES): m/z 231.96 [M+H]⁺.

Synthesis of Compound 24.4

To a solution of compound 24.3 (1.0 g, 4.32 mmol, 1.0 eq) indimethylformamide (10 mL) was added azetidine (0.270 g, 4.75 mmol, 1.1eq) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumtetrafluoroborate (2.77 g, 8.64 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 min under argon atmosphere followed by addition ofpotassium carbonate (1.78 g, 12.96 mmol, 3.0 eq). The reaction mixturewas heated at 100° C. for 10 h. After completion of reaction, reactionmixture was transferred to ice cold water and product was extracted withethyl acetate. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography eluting with 5% methanol in dichloromethane to obtain24.4. (0.8 g, Yield: 68.43%). MS (ES): m/z 271.00 [M+H]⁺.

Synthesis of Compound 24.5

The compound was synthesized from compound 24.4 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 24.5.(0.420 g, Yield: 44.71%). MS (ES): m/z 318.18 [M+H]⁺.

Synthesis of Compound 24.6

The compound was synthesized from Core A and compound 24.5 using GeneralProcedure A to obtain 24.6. (0.310 g, Yield: 33.41%), MS (ES): m/z701.24 [M+H]⁺.

Synthesis of Compound 24.7

The compound was synthesized from compound 24.6 using General ProcedureB to obtain 24.7. (0.150 g, Yield: 89.14%), MS (ES): m/z 381.15 [M+H]⁺.

Synthesis of Compound 24.8

The compound was synthesized from compound 24.7 using General ProcedureC to obtain 24.8. (0.110 g, Yield: 62.20%), MS (ES): m/z 449.18 [M+H]⁺.

Synthesis of Compound 24.9

To a suspension of compound 24.8 (0.110 g, 0.24 mmol, 1.0 eq) in toluene(2 mL) was added tributyltin oxide (0.286 g, 0.48 mmol, 2.0 eq) andreaction mixture was heated at 100° C. for 16 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue which was dissolved in saturated sodium bicarbonatesolution and washed with hexane. Aqueous layer separated and acidifiedwith 1N hydrochloric acid to pH-5-6 and extracted with ethyl acetate.Organic layer was combined, dried over sodium sulfate and concentratedunder reduced pressure to obtain solid which was triturated with hexaneto obtain pure 24.9. (0.060 g, Yield: 56.31%), MS (ES): m/z 435.16[M+H]⁺.

Synthesis of Compound I-24

The compound was synthesized from compound 24.9 and methylamine usingGeneral Procedure H. The material was further purified by columnchromatography and the compound was eluted in 40% ethyl acetate inhexane to obtain I-24 (0.030 g, Yield: 48.54%). MS(ES): m/z 448.37[M+H]⁺ LCMS purity: 99.24%, HPLC purity: 95.14%, ¹H NMR (DMSO-d₆, 400MHz): 12.53 (s, 1H), 11.34 (s, 1H), 8.34-8.32 (d, J=4.4 Hz, 1H),8.06-8.04 (d, J=8.4 Hz, 1H), 7.51 (s, 1H), 7.35-7.33 (d, J=8 Hz, 1H),7.10 (bs, 1H), 6.82 (bs, 1H), 4.41-4.37 (t, J=7.6 Hz, 2H), 4.13-4.08 (m,2H), 4.05 (s, 3H), 2.86-2.85 (d, J=4.4 Hz, 3H), 2.33-2.26 (m, 2H), 1.56(bs, 1H), 1.01-3.96 (m, 4H).

Example 25:7-(cyclopropanecarboxamido)-2-(2-methoxy-4-(pyrrolidine-1-carbonyl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-25)

Synthesis of Compound 25.1

To a solution of compound 24.3 (1.0 g, 4.32 mmol, 1.0 eq) indimethylformamide (10 mL) was added pyrrolidine (0.337 g, 4.75 mmol, 1.1eq) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumtetrafluoroborate (2.77 g, 8.64 mmol, 2.0 eq). The reaction mixture wasdegassed for 10 min under argon atmosphere followed by addition ofpotassium carbonate (1.78 g, 12.96 mmol, 3.0 eq). The reaction mixturewas heated at 100° C. for 10 h. After completion of reaction, reactionmixture was transferred to ice cold water and product was extracted withethyl acetate. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography eluting with 5% methanol in dichloromethane to obtain25.1. (0.810 g, Yield: 65.86%). MS (ES): m/z 285.02 [M+H]⁺.

Synthesis of Compound 25.2

The compound was synthesized from compound 25.1 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 25.2.(0.430 g, Yield: 45.54%). MS (ES): m/z 332.20 [M+H]⁺.

Synthesis of Compound 25.3

The compound was synthesized from Core A and compound 25.2 using GeneralProcedure A to obtain 25.3. (0.4 g, Yield: 43.10%), MS (ES): m/z 715.25[M+H]⁺.

Synthesis of Compound 25.4

The compound was synthesized from compound 25.3 using General ProcedureB to obtain 25.4. (0.180 g, Yield: 81.55%), MS (ES): m/z 395.17 [M+H]⁺.

Synthesis of Compound 25.5

The compound was synthesized from compound 25.4 using General ProcedureC to obtain 25.5. (0.140 g, Yield: 66.33%), MS (ES): m/z 463.19 [M+H]⁺.

Synthesis of Compound 25.6

To a suspension of compound 25.5 (0.140 g, 0.30 mmol, 1.0 eq) in toluene(2 mL) was added tributyltin oxide (0.357 g, 0.6 mmol, 2.0) and reactionmixture was heated at 100° C. for 16 h. After completion of reaction,reaction mixture was concentrated under reduced pressure to obtainresidue which was dissolved in saturated sodium bicarbonate solution andwashed with hexane. Aqueous layer separated and acidified with 1Nhydrochloric acid to pH-5-6 and extracted with ethyl acetate. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain solid which was triturated with hexane toobtain pure 25.6. (0.080 g, Yield: 58.93%), MS (ES): m/z 449.18 [M+H]⁺.

Synthesis of Compound I-25

The compound was synthesized from compound 25.6 and methylamine usingGeneral Procedure H. The material was further purified by columnchromatography and the compound was eluted in 40% ethyl acetate inhexane to obtain I-25 (0.031 g, Yield: 37.65%). MS (ES): m/z 462.56[M+H]⁺ LCMS purity: 100%, HPLC purity: 98.72%, ¹H NMR (DMSO-d₆, 400MHz): 12.49 (s, 1H), 11.31 (s, 1H), 8.32 (s, 1H), 8.15 (s, 1H),8.03-8.01 (d, J=8 Hz, 1H), 7.47 (s, 1H), 7.31 (s, 1H), 7.25-7.23 (d,J=7.6 Hz, 1H), 4.03 (s, 3H), 3.49-3.46 (m, 4H), 2.85 (s, 3H), 1.89-1.83(m, 4H), 1.23 (bs, 1H), 1.00-0.95 (m, 4H).

Example 26:7-(cyclopropanecarboxamido)-2-(2-methoxy-4-(2-oxopyrrolidin-1-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-26)

Synthesis of Compound 26.3

To a solution of compound 26.1 (1.0 g, 4.95 mmol, 1.0 eq) indichloromethane (15 mL) was added potassium hydroxide (0.388 g, 6.93mmol, 1.4 eq) at 0° C. The reaction mixture was stirred at roomtemperature for 1 h. After completion of reaction, The reaction mixturewas poured into dichloromethane and extracted with water. The organiclayer was dried over Na2SO4 and concentrated in vacuo. The residue wasdissolved in 10 mL dichloromethane. Then tetrabutylammonium bromide(0.318 g, 6.93 mmol, 0.2 eq) and KOH (50 percent, 6 ml) were added. Thereaction was stirred for 1 h at room temperature. The reaction mixturewas poured into dichloromethane (50 ml) and extracted with water (3×20ml). The organic layers were dried over Na2SO4 and concentrated in vacuoreaction mixture was transferred into water and product was extractedwith dichloromethane. Organic layer was combined, dried over sodiumsulfate and concentrated under reduced pressure to obtain solid whichwas triturated with pentane to obtain pure 26.3. (0.640 g, 47.87%). MS(ES): m/z 271.00 [M+H]⁺.

Synthesis of Compound 26.4

The compound was synthesized from compound 26.3 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 26.4. (0.3g, 39.92%). MS (ES): m/z 318.18 [M+H]⁺.

Synthesis of Compound 26.5

The compound was synthesized from Core A and compound 26.4 using GeneralProcedure A to obtain 26.5. (0.330 g, 49.79%), MS (ES): m/z 701.24[M+H]⁺.

Synthesis of Compound 26.6

The compound was synthesized from compound 26.5 using General ProcedureB to obtain 26.6. (0.160 g, 89.55%), MS (ES): m/z 381.17 [M+H]⁺.

Synthesis of Compound 26.7

The compound was synthesized from compound 26.6 using General ProcedureC to obtain 26.7. (0.120 g, 63.45%), MS (ES): m/z 449.18 [M+H]⁺.

Synthesis of Compound 26.8

To a suspension of compound 26.7 (0.120 g, 0.26 mmol, 1.0 eq) in toluene(4 mL) was added tributyltin oxide (0.309 g, 0.52 mmol, 2.0 eq) andreaction mixture was heated at 100° C. for 16 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue which was dissolved in saturated sodium bicarbonatesolution and washed with hexane. Aqueous layer separated and acidifiedwith 1N hydrochloric acid to pH-5-6 and extracted with ethyl acetate.Organic layer was combined, dried over sodium sulfate and concentratedunder reduced pressure to obtain solid which was triturated with hexaneto obtain pure 26.8. (0.070 g, 60.22%), MS (ES): 435.36 [M+H]⁺.

Synthesis of Compound I-26

The compound was synthesized from compound 26.8 and methylamine usingGeneral Procedure H. The material was further purified by columnchromatography and the compound was eluted in 40% ethyl acetate inhexane to obtain I-26 (0.028 g, 38.83%). MS (ES): m/z 448.46 [M+H]⁺ LCMSpurity: 100%, HPLC purity: 96.91%, ¹H NMR (DMSO-d₆, 400 MHz): 12.18 (s,1H), 10.84 (s, 1H), 8.26 (s, 1H), 7.89 (bs, 1H), 7.70 (s, 1H), 7.32 (s,1H), 7.11-7.09 (d, J=8.4 Hz, 1H), 6.85-6.83 (d, J=8.4 Hz, 1H), 4.01 (s,3H), 3.95-3.92 (t, J=7.2 Hz, 2H), 3.21 (s, 2H), 2.89-2.88 (d, J=4.4 Hz,3H), 2.17-2.09 (m, 1H), 1.59 (bs, 2H), 1.03-0.94 (m, 4H).

Example 27:7-(cyclopropanecarboxamido)-N-methyl-2-(3-(5-methylpyrazin-2-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-27)

Synthesis of Compound 27.1

The compound was synthesized from 1-bromo-3-nitrobenzene using GeneralProcedure G to obtain 27.1. (3.2 g, Yield: 51.91%). MS (ES): m/z 250.12[M+H]⁺.

Synthesis of Compound 27.3

Argon was purged for 15 min through a stirred mixture of compounds 27.1(3.0 g, 12.00 mmol, 1.0 eq), 27.2 (1.9 g, 15.6 mmol, 1.3 eq), andtripotassium phosphate (6.3 g, 30.0 mmol, 2.5 eq) in 1,4-dioxane (60mL). [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride(0.877 mg, 1.2 mmol, 0.1 eq) was added to it and further purging donefor 10 min. Reaction was stirred at 90° C. for 6 h. After completion ofreaction, reaction mixture was poured over water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain 27.3. (1.5 g, Yield: 57.87%). MS (ES): m/z 216.07[M+H]⁺.

Synthesis of Compound 27.4

To a solution of compound 27.3 (1.5 g, 6.97 mmol, 1.0 eq) in ethanol (15ml) was added tin(II) chloride (1.4 g, 7.6 mmol, 1.1 eq). The reactionwas stirred at room temperature for 2 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain 27.4. (1.1 g, Yield: 85.20%). MS (ES): m/z 186.10[M+H]⁺.

Synthesis of Compound 27.5

To a solution of compound 27.4 (1.1 g, 5.91 mmol, 1.0 eq) inacetonitrile (15 ml) was added tert-butyl nitrite (0.669 g, 6.50 mmol,1.1 eq) and copper(II) bromide (2.6 g, 11.82 mmol, 2.0 eq). The reactionwas stirred at 4° C. for 2 h. After completion of reaction, reactionmixture was transferred into water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtain27.5. (0.7 g, Yield: 47.32%). MS (ES): m/z 249.00 [M+H]⁺.

Synthesis of Compound 27.6

The compound was synthesized from compound 27.5 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 27.6. (0.4g, Yield: 48.06%). MS (ES): m/z 297.17 [M+H]⁺.

Synthesis of Compound 27.7

The compound was synthesized from Core A and compound 27.6 using GeneralProcedure A to obtain 27.7. (0.220 g, Yield: 45.85%), MS (ES): m/z680.23 [M+H]⁺.

Synthesis of Compound 27.8

The compound was synthesized from compound 27.7 using General ProcedureB to obtain 27.8. (0.110 g, Yield: 94.58%), MS (ES): m/z 360.14 [M+H]⁺.

Synthesis of Compound 27.9

The compound was synthesized from compound 27.8 using General ProcedureC to obtain 27.9. (0.1 g, Yield: 76.43%), MS (ES): m/z 428.17 [M+H]⁺.

Synthesis of Compound I-27

The compound was synthesized from compound 27.9 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-27 (0.027 g, Yield: 27.06%). MS (ES): m/z 427.17 [M+H]⁺ LCMS purity:95.11%, HPLC purity: 96.25%, ¹H NMR (DMSO-d₆, 400 MHz): 11.84 (s, 1H),11.14 (s, 1H), 9.30 (s, 1H), 8.70 (s, 1H), 8.63 (s, 1H), 8.32 (s, 1H),8.20-8.18 (d, J=8 Hz, 1H), 7.97-7.95 (d, J=7.6 Hz, 1H), 7.73-7.69 (m,1H), 7.51 (s, 1H), 7.09-7.07 (m, 1H), 2.88-2.87 (d, J=4 Hz, 3H), 2.59(s, 3H), 1.56 (bs, 1H), 1.01-0.87 (m, 4H).

Example 28:7-(cyclopropanecarboxamido)-2-(3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-28)

Synthesis of Compound 28.1

To a solution of 3-bromobenzamide (4.0 g, 20.0 mmol, 1.0 eq) intetrahydrofuran (80 mL) was added Lawesson's reagent (8.8 g, 22.0 mmol,1.1 eq) at 0° C. The reaction was stirred at room temperature for 16 h.After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by combi flash using 3% methanol in dichloromethane aseluant to obtain pure 28.1. (3.0 g, Yield: 69.43%). MS (ES): m/z 215.94[M+H]⁺.

Synthesis of Compound 28.2

To a solution of compound 28.1 (3.0 g, 14.01 mmol, 1.0 eq) in acetone(30 mL) was added methyl iodide (2.1 g, 15.41 mmol, 1.1 eq) and reactionmixture was stirred at room temperature for 2 h. After completion ofreaction, reaction mixture was transferred into ice, stirred andextracted with diethyl ether. Organic layer was combined, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by distillation to obtain pure 28.2.(2.5 g, Yield: 78.25%). MS (ES): m/z 230.95 [M+H]⁺.

Synthesis of Compound 28.3

To a solution of compound 28.2 (2.5 g, 10.86 mmol, 1.0 eq) in ethanol(25 ml) was added acetohydrazide (1.2 g, 16.29 mmol, 1.5 eq). Thereaction was stirred at 100° C. for 18 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 20% ethyl acetate inhexane to obtain 28.3. (1.3 g, Yield: 50.26%). MS (ES): m/z 238.99[M+H]⁺.

Synthesis of Compound 28.4

To a solution of compound 28.3 (1.3 g, 5.46 mmol, 1.0 eq) indimethylformamide (20 mL), was added sodium hydride (0.262 g, 10.92mmol, 2 eq) at 0° C. and stirred for 20 min. Methyl iodide (0.852 g,6.00 mmol, 1.1 eq) was added and reaction mixture was stirred at roomtemperature for 2 h. After completion of reaction, reaction mixture wastransferred into ice, stirred and extracted with diethyl ether. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bydistillation to obtain pure 28.4. (0.7 g, Yield: 50.85%). MS (ES): m/z253.00 [M+H]⁺.

Synthesis of Compound 28.5

The compound was synthesized from compound 28.4 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 28.5. (0.5g, Yield: 60.19%). MS (ES): m/z 300.18 [M+H]⁺.

Synthesis of Compound 28.6

The compound was synthesized from Core A and compound 28.5 using GeneralProcedure A to obtain 28.6. (0.210 g, Yield: 43.57%), MS (ES): m/z683.24 [M+H]⁺.

Synthesis of Compound 28.7

The compound was synthesized from compound 28.6 using General ProcedureB to obtain 28.7. (0.1 g, Yield: 89.72%), MS (ES): m/z 363.15 [M+H]⁺.

Synthesis of Compound 28.8

The compound was synthesized from compound 28.7 using General ProcedureC to obtain 28.8. (0.100 g, Yield: 84.19%), MS (ES): m/z 431.18 [M+H]⁺.

Synthesis of Compound I-28

The compound was synthesized from 28.8 and methylamine using GeneralProcedure D. The material was further purified by column chromatographyeluting with 2.5% methanol in dichloromethane to obtain I-28 (0.027 g,Yield: 27.06%), MS (ES): m/z 430.32 [M+H]⁺ LCMS purity: 100%, HPLCpurity: 96.96%, ¹H NMR (DMSO-d₆, 400 MHz): 11.87 (s, 1H), 11.11 (s, 1H),8.42 (bs, 1H), 8.38-8.37 (d, J=4.4 Hz, 1H), 8.32 (s, 1H), 7.99 (bs, 1H),7.87-7.85 (d, J=7.6 Hz, 1H), 7.64-7.60 (t, J=7.6 Hz, 1H), 7.40 (bs, 1H),3.87 (s, 3H), 2.86-2.85 (d, J=4.4 Hz, 3H), 2.27 (bs, 1H), 1.23 (bs, 3H),1.00-0.93 (m, 4H).

Example 29:7-(cyclopropanecarboxamido)-2-(2-methoxy-4-(methylcarbamoyl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-29)

Synthesis of Compound I-29

The compound was synthesized from compound 24.8 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-29 (0.031 g, Yield: 37.65%), MS (ES): m/z 422.46 [M+H]⁺ LCMS purity:96%, HPLC purity: 95.00%, ¹H NMR (DMSO-d₆, 400 MHz): 12.15 (s, 1H),11.17 (bs, 1H), 11.05 (s, 1H) 8.21 (s, 1H), 7.79-7.78 (d, J=4 Hz, 1H),7.67-7.65 (d, J=8.8 Hz, 1H), 7.09-7.07 (d, J=6.8 Hz, 1H), 6.84-6.82 (d,J=7.6 Hz, 1H), 6.27 (s, 1H), 3.94 (s, 3H), 3.10-3.08 (d, J=5.2 Hz, 3H),2.85-2.84 (d, J=4.4 Hz, 3H), 1.56 (bs, 1H), 0.99-0.95 (m, 4H).

Example 30:7-(cyclopropanecarboxamido)-2-(2-methoxy-4-((4-(methylamino)-4-oxobutyl)amino)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-30)

Synthesis of Compound I-30

The compound was synthesized from compound 26.7 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-30 (0.020 g, Yield: 18.74%), MS (ES): m/z 479.32 [M+H]⁺ LCMS purity:100%, HPLC purity: 100%, ¹H NMR (DMSO-d₆, 400 MHz): 12.15 (s, 1H), 11.17(bs, 1H), 8.21 (s, 1H), 7.79-7.78 (d, J=4 Hz, 1H), 7.67-7.65 (d, J=8.8Hz, 1H), 7.09-7.07 (d, J=6.8 Hz, 1H), 6.84-6.82 (d, J=7.6 Hz, 1H),6.33-6.31 (t, J=6 Hz, 1H), 6.27 (s, 1H), 3.94 (s, 3H), 3.10-3.08 (d,J=5.2 Hz, 2H), 2.85-2.84 (d, J=4.4 Hz, 3H), 2.59-2.58 (d, J=4.4 Hz, 3H),2.21-2.18 (t, J=7.2 Hz, 2H), 1.83-1.80 (t, J=7.2 Hz, 2H), 1.56 (bs, 1H),1.24 (bs, 1H), 0.99-0.95 (m, 4H).

Example 31:7-(cyclopropanecarboxamido)-2-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-31)

Synthesis of Compound 31.2

The compound was synthesized from compound 31.1 using General ProcedureG to obtain 31.2. (0.5 g, Yield: 40.55%). MS (ES): m/z 250.16 [M+H]⁺.

Synthesis of Compound 31.3

The compound was synthesized from Core A and compound 31.2 using GeneralProcedure A to obtain 31.3. (0.220 g, Yield: 55.41%), MS (ES): m/z633.21 [M+H]⁺.

Synthesis of Compound 31.4

The compound was synthesized from compound 31.3 using General ProcedureB to obtain 31.4. (0.1 g, Yield: 92.08%), MS (ES): m/z 313.13[M+H]⁺.

Synthesis of Compound 31.5

The compound was synthesized from compound 31.4 using General ProcedureC to obtain 31.5. (0.060 g, Yield: 49.26%), MS (ES): m/z 381.15 [M+H]⁺.

Synthesis of Compound I-31

The compound was synthesized from compound 1.3 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-31 (0.027 g, Yield: 27.06%), MS (ES): m/z 380.49 [M+H]⁺ LCMS purity:98.07%, HPLC purity: 99.07%, ¹H NMR (DMSO-d₆, 400 MHz): 12.23 (bs, 1H),11.33 (bs, 1H), 8.62 (bs, 1H), 8.46 (bs, 1H), 8.25 (s, 1H), 8.04 (bs,1H), 7.32 (s, 1H), 6.62-6.59 (d, J=9.6 Hz, 1H), 4.08-4.03 (m, 2H),2.88-2.86 (d, J=4.4 Hz, 3H), 1.37-1.31 (m, 3H), 1.26 (s, 1H), 1.03 (bs,4H).

Example 32:7-(cyclopropanecarboxamido)-N-methyl-2-(6-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-32)

Synthesis of Compound 32.2

To a suspension of compound 32.1 (10 g, 54.64 mmol, 1.0 eq) in butanol(100 mL) was added formohydrazide (6.5 g, 109.28 mmol, 2.0) and reactionmixture was heated at 120° C. for 10 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 40% ethyl acetate inhexane to obtain 32.2. (3.6 g, Yield: 29.27%). MS (ES): m/z 225.97[M+H]⁺.

Synthesis of Compound 32.3

To a solution of compound 32.2 (3.6 g, 16.00 mmol, 1.0 eq) indimethylformamide (40 mL), was added sodium hydride (0.768 g, 32.00mmol, 2 eq) at 0° C. and stirred for 20 min. Methyl iodide (2.4 g, 17.6mmol, 1.1 eq) was added and reaction mixture was stirred at roomtemperature for 2 h. After completion of reaction, reaction mixture wastransferred into ice, stirred and extracted with diethyl ether. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bydistillation to obtain pure 32.3. (1.4 g, Yield: 36.61%). MS (ES): m/z238.99 [M+H]⁺.

Synthesis of Compound 32.4

The compound was synthesized from Core C and compound 32.3 using GeneralProcedure E to obtain 32.4. (0.190 g, Yield: 40.86%), MS (ES): m/z670.22 [M+H]⁺.

Synthesis of Compound 32.5

The compound was synthesized from compound 32.4 using General ProcedureB to obtain 32.5. (0.090 g, Yield: 92.23%), MS (ES): m/z 350.13 [M+H]⁺.

Synthesis of Compound 32.6

The compound was synthesized from compound 32.5 using General ProcedureC to obtain 32.6. (0.80 g, Yield: 79.25%), MS (ES): m/z 418.16 [M+H]⁺.

Synthesis of Compound I-32

The compound was synthesized from compound 32.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-32 (0.030 g, Yield: 33.41%), MS (ES): m/z 417.32 [M+H]⁺ LCMS purity:95.84%, HPLC purity: 95.00%, ¹H NMR (DMSO-d₆, 400 MHz): 11.93 (s, 1H),8.65 (s, 1H), 8.47 (bs, 1H), 8.28 (s, 1H), 8.19 (bs, 1H), 8.07 (bs, 1H),7.71 (bs, 1H), 7.07 (bs, 1H), 6.82 (bs, 1H), 3.94 (s, 3H), 3.13 (bs,3H), 1.54 (bs, 1H), 1.02 (bs, 4H).

Example 33:7-(cyclopropanecarboxamido)-2-(2-ethoxypyridin-3-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-33)

Synthesis of Compound 33.2

The compound was synthesized from compound 33.1 using General ProcedureG to obtain 33.2. (0.450 g, Yield: 36.50%). MS (ES): m/z 250.16 [M+H]⁺.

Synthesis of Compound 33.3

To a solution of Core A (0.450 g, 0.70 mmol, 1.0 eq) in 1,4 dioxane (6mL) was added compound 33.2 (0.210 g, 0.84 mmol, 1.2 eq) and cesiumcarbonate (0.455 g, 1.4 mmol, 2.0 eq). The reaction mixture was degassedfor 10 min. under argon atmosphere, then palladium(II) acetate (0.235 g,1.05 mmol, 1.5 eq) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.033 g, 0.07mmol, 0.1 eq) were added, again degassed for 5 min. The reaction wasstirred at 100° C. for 4 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 3% methanol in dichloromethane as eluantto obtain pure 33.3. (0.2 g, Yield: 44.78%). MS (ES): m/z 633.21 [M+H]⁺.

Synthesis of Compound 33.4

The compound was synthesized from compound 33.3 using General ProcedureB to obtain 33.4. (0.098 g, Yield: 99.27%), MS (ES): m/z 313.13 [M+H]⁺.

Synthesis of Compound 33.5

The compound was synthesized from compound 33.4 using General ProcedureC to obtain 33.5. (0.1 g, Yield: 74.64%), MS (ES): m/z 381.15 [M+H]⁺.

Synthesis of Compound I-33

The compound was synthesized from compound 33.5 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-33 (0.028 g, Yield: 28.07%), MS (ES): m/z 380.64 [M+H]⁺ LCMS purity:97.05%, HPLC purity: 96.49%, ¹H NMR (DMSO-d₆, 400 MHz): 12.23 (bs, 1H),11.33 (bs, 1H), 8.41-8.40 (d, J=7.2 Hz, 1H), 8.35 (bs, 1H), 8.29 (s,1H), 8.23 (bs, 1H), 7.53 (bs, 1H), 7.18 (bs, 1H), 4.59-4.53 (m, 2H),2.86-2.85 (d, J=3.6 Hz, 3H), 2.25 (bs, 1H), 1.51-1.47 (t, J=6.8 Hz, 3H),0.97-0.95 (m, 4H).

Example 34:7-(cyclopropanecarboxamido)-2-(2-cyclopropoxypyridin-3-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-34)

Synthesis of Compound 34.2

To a solution of compound 34.1 (2.0 g, 9.00 mmol, 1.0 eq) intetrahydrofuran (20 mL), was added cyclopropanol (0.574 g, 9.9 mmol, 1.1eq). Sodium hydride (0.432 g, 18.0 mmol, 2 eq) was added at 0° C.Reaction mixture was stirred at room temperature for 2 h. Aftercompletion of reaction, reaction mixture was transferred into ice-water,extracted with diethyl ether. Organic layer was combined, dried oversodium sulfate and concentrated under reduced pressure to obtain crude.This was further purified by distillation to obtain pure 34.2. (1.0 g,Yield: 42.71%). MS (ES): m/z 261.97 [M+H]⁺.

Synthesis of Compound 34.3

The compound was synthesized from compound 34.2 using General ProcedureG to obtain 34.3. (0.4 g, Yield: 39.99%). MS (ES): m/z 262.16 [M+H]⁺.

Synthesis of Compound 34.4

To a solution of Core A (0.450 g, 0.70 mmol, 1.0 eq) in 1,4-dioxane (6mL) was added compound 34.3 (0.219 g, 0.84 mmol, 1.2 eq) and cesiumcarbonate (0.455 g, 1.4 mmol, 2.0 eq). The reaction mixture was degassedfor 10 min. under argon atmosphere, then palladium(II) acetate (0.235 g,1.05 mmol, 1.5 eq) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.033 g, 0.07mmol, 0.1 eq) were added, again degassed for 5 min. The reaction wasstirred at 100° C. for 4 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 3% methanol in dichloromethane as eluantto obtain pure 34.4. (0.180 g, Yield: 39.55%). MS (ES): m/z 645.21[M+H]⁺.

Synthesis of Compound 34.5

The compound was synthesized from compound 34.4 using General ProcedureB to obtain 34.5. (0.090 g, Yield: 99.39%), MS (ES): m/z 325.13 [M+H]⁺.

Synthesis of Compound 34.6

The compound was synthesized from compound 34.5 using General ProcedureC to obtain 34.6. (0.080 g, Yield: 64.83%), MS (ES): m/z 393.15 [M+H]⁺.

Synthesis of Compound I-34

The compound was synthesized from compound 34.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-34 (0.026 g, Yield: 32.58%), MS (ES): m/z 392.57 [M+H]⁺ LCMS purity:99.56%, HPLC purity: 99.20%, ¹H NMR (DMSO-d₆, 400 MHz): 12.03 (s, 1H),11.63 (s, 1H), 8.43-8.42 (d, J=6 Hz, 1H), 8.35-8.34 (d, J=4.4 Hz, 1H),8.29 (s, 2H), 7.53 (bs, 1H), 7.24-7.22 (m, 1H), 4.57-4.54 (m, 1H),2.86-2.85 (d, J=3.6 Hz, 3H), 2.25 (bs, 1H), 1.06-0.97 (m, 6H), 0.86-0.80(m, 2H).

Example 35:7-(cyclopropanecarboxamido)-N-(methyl-d₃)-2-(6-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-35)

Synthesis of Compound I-35

The compound was synthesized from compound 32.6 and methyl-d₃-amineusing General Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-35 (0.027 g, Yield: 22.39%), MS (ES): m/z 420.72 [M+H]⁺ LCMS purity:96.23%, HPLC purity: 97.86%, ¹H NMR (DMSO-d₆, 400 MHz): 11.79 (s, 1H),11.32 (s, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.15-8.12 (m,1H), 8.05-8.04 (d, J=3.6 Hz, 2H), 7.67 (s, 1H), 4.01 (s, 3H), 2.27 (bs,1H), 1.06-0.96 (m, 4H).

Example 36:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-36)

Synthesis of Compound 36.2

To a solution of compound 36.1 (1.0 g, 4.56 mmol, 1.0 eq) indichloromethane (15 mL) was added thionyl chloride (3.28 mL, 45.6 mmol,10.0 eq) at 0° C. with catalytic dimethylformamide (0.5 mL). Reactionmixture was stirred at 70° C. for 2 h. After completion of reaction,reaction mixture was concentrated under reduced pressure to obtain crudematerial. To this crude material was added 20 ml ethyl acetate followedby 20 mL aqueous ammonia solution and stirred at room temperature for 1h. The organic layer was separated, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatography using30% ethyl acetate in hexane to obtain 36.2. (0.850 g, Yield: 85.38%), MS(ES): m/z 218.95 [M+H]⁺.

Synthesis of Compound 36.3

To a solution of compound 36.2 (0.850 g, 3.89 mmol, 1.0 eq) indimethylformamide (10 mL) was added dimethylformamide dimethylacetal(0.555 g, 4.66 mmol, 1.2 eq). Reaction mixture was heated at 120° C. for1 h. After completion of reaction, reaction mixture was cooled and wasadded acetic acid (8 mL) followed by hydrazine hydrate (0.972 g, 19.45mmol, 5.0 eq) and again heated at 120° C. for 2 h. After completion ofreaction, reaction mixture was transferred to ice cold water and productwas extracted with ethyl acetate. Organic layer was combined, washedwith brine solution, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bycolumn chromatography eluting with 40% ethyl acetate in hexane to obtain36.3. (0.7 g, Yield: 74.18%), MS (ES): m/z 242.96 [M+H]⁺.

Synthesis of Compound 36.4

To a solution of compound 36.3 (0.450 g, 1.85 mmol, 1.0 eq) indimethylformamide (5 mL), was added methyl iodide (0.288 g, 2.03 mmol,1.1 eq). Sodium hydride (0.088 g, 3.7 mmol, 2.0 eq) was added at 0° C.Reaction mixture was stirred at room temperature for 2 h. Aftercompletion of reaction, reaction mixture was transferred into ice,stirred and extracted with diethyl ether. Organic layer was combined,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by distillation toobtain pure 36.4. (0.472 g, Yield: 99.14%). MS (ES): m/z 256.98 [M+H]⁺.

Synthesis of Compound 36.5

The compound was synthesized from compound 36.4 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 36.5. (0.4g, Yield: 67.58%). MS (ES): m/z 304.16 [M+H]⁺.

Synthesis of Compound 36.6

The compound was synthesized from Core A and compound 36.5 using GeneralProcedure A to obtain 36.6. (0.210 g, Yield: 43.32%), MS (ES): m/z687.21 [M+H]⁺.

Synthesis of Compound 36.7

The compound was synthesized from compound 36.6 using General ProcedureB to obtain 36.7. (0.115 g, Yield: 98.19%), MS (ES): m/z 367.13 [M+H]⁺.

Synthesis of Compound 36.8

The compound was synthesized from compound 36.7 using General ProcedureC to obtain 36.8. (0.110 g, Yield: 77.30%), MS (ES): m/z 435.15 [M+H]⁺.

Synthesis of Compound I-36

The compound was synthesized from compound 36.8 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-36 (0.025 g, Yield: 22.78%), MS (ES): m/z 434.56 [M+H]⁺ LCMS purity:97.82%, HPLC purity: 97.68%, ¹H NMR (DMSO-d₆, 400 MHz): 12.10 (s, 1H),11.32 (bs, 1H), 8.65 (bs, 1H), 8.39 (bs, 1H), 8.32 (bs, 1H), 8.05-8.03(m, 2H), 7.51-7.48 (m, 2H), 3.99 (s, 3H), 2.85 (bs, 3H), 2.23 (bs, 1H),0.99-0.95 (m, 4H).

Example 37:7-(cyclopropanecarboxamido)-2-(2-ethoxy-5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-37)

Synthesis of Compound 37.1

To a solution of 5-bromo-2-chloro-3-nitropyridine (5.0 g, 21.09 mmol,1.0 eq) in ethanol (250 mL) was added dropwise sodium ethoxide (8.3 mL,21% ethanol solution, 1.2 eq). Reaction mixture was stirred and heatedat 80° C. for 1 h. After completion of reaction, reaction mixture wascooled to room temperature, transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain 37.1 (3.0 g, Yield: 57.67%). MS (ES): m/z 246.97[M+H]⁺.

Synthesis of Compound 37.2

The compound was synthesized from compound 37.1 using General ProcedureG to obtain 37.2. (2.3 g, Yield: 64.40%). MS (ES): m/z 295.14 [M+H]⁺.

Synthesis of Compound 37.3

The compound was synthesized from compound 37.2 and3-bromo-1-methyl-1H-pyrazole using General Procedure A to obtain 37.3.(1.5 g, Yield: 77.27%), MS (ES): m/z 249.09 [M+H]⁺.

Synthesis of Compound 37.4

To a solution of compound 37.3 (1.5 g, 6.04 mmol, 1.0 eq) in methanol(30 ml), palladium on charcoal (0.8 g) was added. Hydrogen was purgedthrough reaction mixture for 4 h at room temperature. After completionof reaction, reaction mixture was filtered through Celite bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 37.4. (1.1 g, 83.41%). MS (ES): m/z 219.11[M+H]⁺.

Synthesis of Compound 37.5

To the compound 37.4 (1.1 g, 5.02 mmol, 1.0 eq) was added 30%hydrobromic acid (2.2 mL) dropwise at 0° C. Sodium nitrite (0.692 g,10.04 mmol, 2.0 eq) and acetone (8.8 mL) were added to this reactionmixture and stirred for 2 min. Then copper(I) bromide (1.4 g, 10.04mmol, 2.0 eq) was added and reaction mixture was stirred for 15 min.After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain 37.5. (0.7 g, Yield:49.23%). MS (ES): m/z 282.02 [M+H]⁺.

Synthesis of Compound 37.6

The compound was synthesized from compound 37.5 using General ProcedureG to obtain 37.6. (0.4 g, Yield: 57.14%). MS (ES): m/z 330.19 [M+H]⁺.

Synthesis of Compound 37.7

The compound was synthesized from Core A and compound 37.6 using GeneralProcedure A to obtain 37.7. (0.2 g, Yield: 39.75%), MS (ES): m/z 713.25[M+H]⁺.

Synthesis of Compound 37.8

The compound was synthesized from compound 37.7 using General ProcedureB to obtain 37.8. (0.1 g, Yield: 90.82%), MS (ES): m/z 393.16 [M+H]⁺.

Synthesis of Compound 37.9

The compound was synthesized from compound 37.8 using General ProcedureC to obtain 37.9. (0.095 g, Yield: 80.96%), MS (ES): m/z 461.19 [M+H]⁺.

Synthesis of Compound 1-37

The compound was synthesized from compound 37.9 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-37 (0.080 g, Yield: 84.39%), MS (ES): m/z 460.96 [M+H]⁺ LCMS purity:100%, HPLC purity: 99.73%, ¹H NMR (DMSO-d₆, 400 MHz): 12.27 (s, 1H),11.34 (s, 1H), 8.66 (bs, 1H), 8.64-8.63 (d, J=2 Hz, 1H), 8.39-8.38 (d,J=4.4 Hz, 1H), 8.30 (s, 1H), 7.80-7.80 (d, J=2 Hz, 1H), 7.60 (bs, 1H),6.89 (bs, 1H), 4.61-4.55 (m, 2H), 3.93 (s, 3H), 2.86-2.85 (d, J=4.8 Hz,3H), 2.24 (bs, 1H), 1.52-1.48 (t, J7.2 Hz, 3H), 0.98-0.95 (m, 4H).

Example 38:7-(cyclopropanecarboxamido)-2-(2-cyclopropoxy-5-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-38)

Synthesis of Compound 38.1

To a solution of 5-bromo-2-chloro-3-nitropyridine (1.0 g, 4.21 mmol, 1.0eq) in dimethylformamide (10 mL), was added sodium hydride (0.202 g,8.42 mmol, 2 eq) at 0° C. and stirred for 20 min. Cyclopropanol (0.268g, 4.63 mmol, 1.1 eq) was added and reaction mixture was stirred at roomtemperature for 2 h. After completion of reaction, reaction mixture wastransferred into ice, stirred and extracted with diethyl ether. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bydistillation to obtain pure 38.1. (0.34 g, Yield: 31.16%). MS (ES): m/z259.96 [M+H]⁺.

Synthesis of Compound 38.3

The compound was synthesized from compounds 38.1 and 38.2 using GeneralProcedure A to obtain 38.3. (1.2 g, Yield: 74.66%), MS (ES): m/z 261.09[M+H]⁺.

Synthesis of Compound 38.4

To a solution of compound 38.3 (1.2 g, 4.61 mmol, 1.0 eq) in methanol(25 ml), palladium on charcoal (0.6 g) was added. Hydrogen was purgedthrough reaction mixture for 4 h at room temperature. After completionof reaction, reaction mixture was filtered through Celite-bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 38.4. (0.9 g, Yield: 84.77%). MS (ES): m/z231.12 [M+H]⁺.

Synthesis of Compound 38.5

To compound 38.4. (0.9 g, 3.89 mmol, 1.0 eq) was added 30% hydrobromicacid (1.8 mL) dropwise at 0° C. Sodium nitrite (0.536 g, 7.78 mmol, 2.0eq) and acetone (7.2 mL) were added to this reaction mixture and stirredfor 2 min. Then copper(I) bromide (1.1 g, 7.78 mmol, 2.0 eq) was addedand reaction mixture was stirred for 15 min. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain 38.5. (0.540 g, Yield: 46.97%). MS (ES): m/z 295.01[M+H]⁺.

Synthesis of Compound 38.6

The compound was synthesized from compound 38.5 using General ProcedureG to obtain 38.6. (0.4 g, Yield: 63.86%). MS (ES): m/z 342.19 [M+H]⁺.

Synthesis of Compound 38.7

The compound was synthesized from Core A and compound 38.6 using GeneralProcedure A to obtain 38.7. (0.230 g, Yield: 44.95%), MS (ES): m/z725.25 [M+H]⁺.

Synthesis of Compound 38.8

The compound was synthesized from compound 38.7 using General ProcedureB to obtain 38.8. (0.115 g, Yield: 89.61%), MS (ES): m/z 405.16 [M+H]⁺.

Synthesis of Compound 38.9

The compound was synthesized from compound 38.8 using General ProcedureC to obtain 38.9. (0.1 g, Yield: 74.43%), MS (ES): m/z 473.19 [M+H]⁺.

Synthesis of Compound I-38

The compound was synthesized from compound 38.9 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-38 (0.074 g, Yield: 74.15%), MS (ES): m/z 472.82 [M+H]⁺ LCMS purity:96.41%, HPLC purity: 95.48%, ¹H NMR (DMSO-d₆, 400 MHz): 12.07 (s, 1H),11.35 (s, 1H), 8.67 (bs, 2H), 8.38 (bs, 1H), 8.30 (s, 1H), 7.80 (bs,1H), 7.60 (bs, 1H), 6.90 (bs, 1H), 4.59 (bs, 1H), 3.94 (s, 3H),2.86-2.85 (d, J=4.8 Hz, 3H), 1.23 (bs, 2H), 1.08-1.02 (m, 5H), 0.83 (bs,2H).

Example 39:7-(cyclopropanecarboxamido)-2-(2-cyclopropoxy-5-(thiazol-2-yl)pyridin-3-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-39)

Synthesis of Compound 39.2

To a solution of 38.1 (1.1 g, 4.24 mmol, 1.0 eq) in 1,4-dioxane (15 mL)was added bis(pinacolato)diboron (1.2 g, 5.08 mmol, 1.2 eq). Thereaction mixture was degassed for 10 min. under argon atmosphere, thentetrakis(triphenylphosphine)palladium(0) (0.489 g, 0.42 mmol, 0.1 eq)and compound 39.1 (1.5 g, 5.08 mmol, 1.0 eq) added, again degassed for 5min. The reaction was stirred at 95° C. for 4 h. After completion ofreaction, reaction mixture was cooled to room temperature, transferredinto water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by combi flash using 3% methanol in dichloromethane aseluant to obtain pure 39.2. (1.1 g, Yield: 77.31%). MS (ES): m/z 264.04[M+H]⁺.

Synthesis of Compound 39.3

To a solution of compound 39.2 (1.1 g, 4.16 mmol, 1.0 eq) in methanol(15 ml), palladium on charcoal (0.4 g) was added. Hydrogen was purgedthrough reaction mixture for 4 h at room temperature. After completionof reaction, reaction mixture was filtered through Celite-bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 39.3. (0.8 g, Yield: 82.07%). MS (ES): m/z234.07 [M+H]⁺.

Synthesis of Compound 39.4

To the compound 39.3. (0.8 g, 3.41 mmol, 1.0 eq) was added 30%hydrobromic acid (1.6 mL) dropwise at 0° C. Sodium nitrite (0.536 g,7.78 mmol, 2.0 eq) and acetone (6.4 mL) were added to this reactionmixture and stirred for 2 min. Then copper(I) bromide (0.975 g, 6.82mmol, 2.0 eq) was added and reaction mixture was stirred for 15 min.After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain 39.4. (0.5 g, Yield:49.06%). MS (ES): m/z 296.97 [M+H]⁺.

Synthesis of Compound 39.5

The compound was synthesized from compound 39.4 using General ProcedureG to obtain 39.5. (0.4 g, Yield: 69.06%). MS (ES): m/z 345.14 [M+H]⁺.

Synthesis of Compound 39.6

The compound was synthesized from Core A and compound 39.5 using GeneralProcedure A to obtain 39.6. (0.180 g, Yield: 35.03%), MS (ES): m/z728.20 [M+H]⁺.

Synthesis of Compound 39.7

The compound was synthesized from compound 39.6 using General ProcedureB to obtain 39.7. (0.090 g, Yield: 89.32%), MS (ES): m/z 408.11 [M+H]⁺.

Synthesis of Compound 39.8

The compound was synthesized from compound 39.7 using General ProcedureC to obtain 39.8. (0.080 g, Yield: 76.16%), MS (ES): m/z 476.13 [M+H]⁺.

Synthesis of Compound I-39

The compound was synthesized from compound 39.8 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-39 (0.069 g, Yield: 86.43%), MS (ES): m/z 475.82 [M+H]⁺ LCMS purity:98.79%, HPLC purity: 96.44%, ¹H NMR (DMSO-d₆, 400 MHz): 12.13 (s, 1H),11.39 (s, 1H), 8.86 (bs, 1H), 8.80 (bs, 1H), 8.38 (bs, 1H), 8.32 (bs,1H), 8.01 (bs, 1H), 7.90 (bs, 1H), 7.65 (bs, 1H), 4.64 (bs, 1H),2.87-2.86 (d, J=4.8 Hz, 3H), 1.24 (bs, 4H), 1.12 (bs, 1H), 0.87-0.86 (m,4H).

Example 40:7-(cyclopropanecarboxamido)-2-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-40)

Synthesis of Compound 40.2

Argon was purged for 15 min through a stirred mixture of compound 40.1(2.0 g, 11.49 mmol, 1.0 eq), sodium carbonate (3.6 g, 34.4 mmol, 3.0eq), cyclopropyl boronic acid (1.2 g, 14.93 mmol, 1.3 eq) and cupricacetate (5.1 g, 28.72 mmol, 2.5 eq) in 1,2-dichloroethane (80 mL).2,2′-Bipyridine (0.182 mg, 1.17 mmol, 0.5 eq) was added to it andfurther purging done for 10 min. Reaction was allowed to stir at 50° C.for 6 h. After completion of reaction, reaction mixture was poured overwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain 40.2. (1.0 g, Yield:40.64%). MS (ES): m/z 213.98 [M+H]⁺.

Synthesis of Compound 40.3

The compound was synthesized from compound 40.2 using General ProcedureG to obtain 40.3. (0.4 g, Yield: 36.43%). MS (ES): m/z 262.16 [M+H]⁺.

Synthesis of Compound 40.4

The compound was synthesized from Core A and compound 40.3 using GeneralProcedure A to obtain 40.4. (0.2 g, Yield: 43.94%), MS (ES): m/z 645.21[M+H]⁺.

Synthesis of Compound 40.5

The compound was synthesized from compound 40.4 using General ProcedureB to obtain 40.5. (0.1 g, Yield: 99.39%), MS (ES): m/z 325.13 [M+H]⁺.

Synthesis of Compound 40.6

The compound was synthesized from compound 40.5 using General ProcedureC to obtain 40.6. (0.090 g, Yield: 67.62%), MS (ES): m/z 393.15 [M+H]⁺.

Synthesis of Compound I-40

The compound was synthesized from compound 40.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-40 (0.026 g, Yield: 32.58%), MS (ES): m/z 392.51 [M+H]⁺ LCMS purity:98.14%, HPLC purity: 98.14%, ¹H NMR (DMSO-d₆, 400 MHz): 11.34 (s, 1H),10.94 (s, 1H), 8.30-8.28 (d, J=4.4 Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H),7.88-7.87 (d, J=2.4 Hz, 1H), 7.18 (s, 1H), 6.55-6.53 (d, J=9.6 Hz, 1H),3.44-3.40 (m, 1H), 2.84-2.83 (d, J=4.4 Hz, 3H), 2.17 (bs, 1H), 1.07-1.03(m, 2H), 1.00-0.97 (m, 4H), 0.90 (m, 2H).

Example 41:2-(3-(azetidin-1-yl)-2-cyanophenyl)-7-(cyclopropanecarboxamido)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-41)

Synthesis of Compound 41.2

To a solution of 41.1 (1.0 g, 5.00 mmol, 1.0 eq) and azetidine (0.855 g,15.00 mmol, 3.0 eq) in dimethyl sulphoxide (15 mL) was added potassiumcarbonate (1.3 g, 10.0 mmol, 2.0 eq) and reaction mixture heated at 190°C. for 10 h. After completion of reaction, reaction mixture wastransferred into ice cold water and product was extracted with ethylacetate. Organic layer was combined and dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and compound was eluted in 25%ethyl acetate in hexane to obtain pure 41.2 (0.6 g, Yield: 50.61%). MS(ES): m/z 237.99 [M+H]⁺.

Synthesis of Compound 41.3

The compound was synthesized from compound 41.2 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 41.3. (0.5g, Yield: 69.53%). MS (ES): m/z 285.17 [M+H]⁺.

Synthesis of Compound 41.4

The compound was synthesized from Core A and compound 41.3 using GeneralProcedure A to obtain 41.4. (0.3 g, Yield: 63.64%), MS (ES): m/z 668.23[M+H]⁺.

Synthesis of Compound 41.5

The compound was synthesized from compound 41.4 using General ProcedureB to obtain 41.5. (0.130 g, Yield: 83.30%), MS (ES): m/z 348.14 [M+H]⁺.

Synthesis of Compound 41.6

The compound was synthesized from compound 41.5 using General ProcedureC to obtain 41.6. (0.110 g, Yield: 70.75%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound I-41

The compound was synthesized from compound 41.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-41 (0.035 g, Yield: 31.89%), MS (ES): m/z 415.82 [M+H]⁺ LCMS purity:99.19%, HPLC purity: 99.50%, ¹H NMR (DMSO-d₆, 400 MHz): 11.66 (s, 1H),11.21 (s, 1H), 8.41-8.40 (d, J=4.4 Hz, 1H), 8.32 (s, 1H), 7.57-7.53 (t,J=7.6 Hz, 1H), 7.42-7.41 (d, J=2 Hz, 1H), 7.03-7.01 (d, J=7.2 Hz, 1H),6.68-6.66 (d, J=8.4 Hz, 1H), 4.21-4.18 (t, J=7.2 Hz, 4H), 2.83-2.82 (d,J=4.4 Hz, 3H), 2.38-2.32 (m, 2H), 2.21 (bs, 1H), 0.95-0.90 (m, 4H).

Example 42:2-(4-(azetidine-1-carbonyl)-2-fluorophenyl)-7-(cyclopropanecarboxamido)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-42)

Synthesis of Compound 42.2

The compound was synthesized from compound 42.1 and azetidinehydrochloride using General Procedure H to obtain 42.2 (0.7 g, Yield:59.40%). MS (ES): m/z 258.98 [M+H]⁺.

Synthesis of Compound 42.3

The compound was synthesized from compound 42.2 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 42.3. (0.4g, Yield: 56.38%). MS (ES): m/z 306.16 [M+H]⁺.

Synthesis of Compound 42.4

The compound was synthesized from Core A and compound 42.3 using GeneralProcedure A to obtain 42.4. (0.280 g, Yield: 57.59%), MS (ES): m/z689.22 [M+H]⁺.

Synthesis of Compound 42.5

The compound was synthesized from compound 42.4 using General ProcedureB to obtain 42.5. (0.149 g, Yield: 99.50%), MS (ES): m/z 369.13 [M+H]⁺.

Synthesis of Compound 42.6

The compound was synthesized from compound 42.5 using General ProcedureC to obtain 42.6. (0.130 g, Yield: 73.15%), MS (ES): m/z 437.16 [M+H]⁺.

Synthesis of Compound 42.7

To a suspension of compound 42.6 (0.130 g, 0.29 mmol, 1.0 eq) in toluene(2 mL) was added tributyltin oxide (0.345 g, 0.58 mmol, 2.0 eq) andreaction mixture was heated at 100° C. for 16 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue which was dissolved in saturated sodium bicarbonatesolution and washed with hexane. Aqueous layer separated and acidifiedwith 1N hydrochloric acid to pH-5-6 and extracted with ethyl acetate.Organic layer was combined, dried over sodium sulfate and concentratedunder reduced pressure to obtain solid which was triturated with hexaneto obtain pure 42.7. (0.070 g, Yield: 55.63%), MS (ES): m/z 423.14[M+H]⁺.

Synthesis of Compound I-42

The compound was synthesized from compound 42.7 using General ProcedureH to obtain I-42 (0.025 g, 34.64%), MS (ES): 436.82 [M+H]⁺ LCMS purity:100%, HPLC purity: 99.48%, ¹H NMR (DMSO-d₆, 400 MHz): 12.15 (s, 1H),11.33 (s, 1H), 8.40-8.39 (d, J=4.8 Hz, 1H), 8.32 (s, 1H), 8.07-8.03 (t,J=8 Hz, 2H), 7.64-7.60 (m, 1H), 7.53 (s, 1H), 4.40-4.37 (t, J=7.6 Hz,2H), 4.09-4.05 (t, J=7.6 Hz, 2H), 2.84-2.83 (d, J=4.4 Hz, 3H), 2.32-2.24(m, 3H), 0.98-0.93 (m, 4H).

Example 43:7-(cyclopropanecarboxamido)-N-methyl-2-(2-oxo-1-(tetrahydro-2H-pyran-3-yl)-1,2-dihydropyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-43)

Synthesis of Compound 43.1

To a solution of 3,4-dihydro-2H-pyran (20.0 g, 238.09 mmol, 1.0 eq) indichloromethane (200 mL) was added dropwise bromine in dichloromethane(37.8 g, 11.90 mmol, 1.0 eq) at −78° C. The reaction was stirred at roomtemperature for 10 h. After completion of reaction, reaction mixture wasconcentrated under reduced pressure and added diethyl ether andfiltered. Filtrate was concentrated under reduced pressure to obtaincrude material. This was further purified by vacuum distillation toobtain pure 43.1. (16.0 g, Yield: 41.28%). MS (ES): m/z 163.97 [M+H]⁺.

Synthesis of Compound 43.3

To a solution of compound 43.1 (16.0 g, 98.15 mmol, 1 eq) and compound43.2 (12.9 g, 117.78 mmol, 1.2 eq) in 1,4-dioxane (250 mL) was addedpotassium carbonate (27.0 g, 196.3 mmol, 2.0 eq) and degassed with argonfor 15 min. Copper iodide (3.7 g, 19.63 mmol, 0.2 eq) and1,2-dimethylethylenediamine (3.4 g, 39.26 mmol, 0.4 eq) was added andreaction mixture again degassed with argon for 5 min followed by heatingat 110° C. for 12 h. After completion of reaction, reaction mixture wascooled to room temperature, transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and compound was eluted in 1.2% methanol indichloromethane to obtain pure 43.3. (7.0 g, Yield: 37.10%). MS (ES):m/z 193.09 [M+H]⁺.

Synthesis of Compound 43.4

To a solution of compound 43.3 (7.0 g, 36.26 mmol, 1.0 eq) in ethylacetate and tetrahydrofuran (1:1.70 mL), 10% palladium on charcoal (1.8g) was added. Hydrogen was purged through reaction mixture for 4 h atroom temperature. After completion of reaction, reaction mixture wasfiltered through Celite-bed and washed with methanol. Filtrate wasconcentrated under reduced pressure to obtain crude material. This wasfurther purified by trituration with n-pentane to obtain pure 43.4. (4.1g, Yield: 57.96%). MS (ES): m/z 195.11 [M+H]⁺.

Synthesis of Compound 43.5

To a solution of compound 43.4 (4.1 g, 21.13 mmol, 1.0 eq) inacetonitrile (70 mL) were added tert-butyl nitrite (2.3 g, 23.24 mmol,1.1 eq) and copper(II) bromide (4.7 g, 21.13 mmol, 1.0 eq) undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 10 min. After completion of reaction, reaction mixturewas transferred into water and product was extracted with ethyl acetate.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography andcompound was eluted in 20% ethyl acetate in hexane to obtain pure 43.5.(1.1 g, Yield: 20.19%). MS (ES): m/z 259.00 [M+H]⁺.

Synthesis of Compound 43.6

The compound was synthesized from compounds B.2 and 43.5 using GeneralProcedure A to obtain 43.6. (0.380 g, Yield: 38.35%), MS (ES): m/z549.25 [M+H]⁺.

Synthesis of compound 43.7 To a solution of compound 43.6 (0.380 g, 0.69mmol, 1.0 eq), in methanol (5 mL) was added sodium hydroxide (0.138 g,3.45 mmol, 5.0 eq). The reaction mixture was stirred at 60° C. for 1 h.After completion of reaction, reaction mixture was concentrated underreduced pressure to obtain residue. To this added water and acidifiedwith 1N hydrochloric acid to adjust pH-6 at 10° C. Product was extractedwith dichloromethane. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 43.7. (0.3 g, Yield: 81.02%). MS (ES):m/z 535.23 [M+H]⁺.

Synthesis of Compound 43.8

The compound was synthesized from compound 43.7 and methylamine usingGeneral Procedure H to obtain 43.8. (0.250 g, Yield: 81.35%). MS (ES):m/z 548.26 [M+H]⁺.

Synthesis of Compound 43.9

The compound was synthesized from compound 43.8 using General ProcedureB to obtain 43.9. (0.130 g, Yield: 77.51%), MS (ES): m/z 368.17 [M+H]⁺.

Synthesis of Compound I-43

The compound was synthesized from compound 43.9 using General ProcedureC to obtain I-43. (0.090 g, Yield: 58.41%), MS (ES): m/z 436.77 [M+H]⁺LCMS purity: 100%, HPLC purity: 98.75%, CHIRAL HPLC: 48.42%, 51.58%, ¹HNMR (DMSO-d₆, 400 MHz): 12.63 (s, 1H), 11.15 (s, 1H), 8.30-8.26 (m, 2H),8.03-8.02 (d, J=5.2 Hz, 1H), 7.45 (bs, 1H), 6.55-6.54 (d, J=6.8 Hz, 1H),5.03 (bs, 1H), 3.87 (bs, 2H), 3.59-3.49 (m, 3H), 2.85-2.84 (d, J=4.4 Hz,2H), 2.21 (bs, 1H), 2.01 (bs, 2H), 1.91 (s, 1H), 1.79 (bs, 2H),0.97-0.93 (m, 4H).

Example 44:7-(cyclopropanecarboxamido)-2-(4-cyclopropoxypyridin-3-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-44)

Synthesis of Compound 44.2

To a solution of compound 44.1 (6.0 g, 37.97 mmol, 1.0 eq) indimethylformamide (80 mL), was added sodium hydride (1.8 g, 75.94 mmol,2 eq) at 0° C. and stirred for 20 min. Cyclopropanol (2.4 g, 41.76 mmol,1.1 eq) was added and reaction mixture was stirred at room temperaturefor 2 h. After completion of reaction, reaction mixture was transferredinto ice, stirred and extracted with diethyl ether. Organic layer wascombined, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified bydistillation to obtain pure 44.2. (4.3 g, Yield: 63.07%). MS (ES): m/z181.06 [M+H]⁺.

Synthesis of Compound 44.3

To a solution of compound 44.2 (4.3 g, 23.88 mmol, 1.0 eq) in methanol(45 ml), palladium on charcoal (1.9 g) was added. Hydrogen was purgedthrough reaction mixture for 4 h at room temperature. After completionof reaction, reaction mixture was filtered through Celite-bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 44.3. (3.5 g, Yield: 97.65%). MS (ES): m/z151.08 [M+H]⁺.

Synthesis of Compound 44.4

To the compound 44.3 (3.5 g, 23.17 mmol, 1.0 eq) was added 30%hydrobromic acid (6.0 mL) dropwise at 0° C. Sodium nitrite (3.1 g, 46.34mmol, 2.0 eq) and acetone (25 mL) were added to this reaction mixtureand stirred for 2 min. Then copper(I) bromide (6.6 g, 46.34 mmol, 2.0eq) was added and reaction mixture was stirred for 15 min. Aftercompletion of reaction, reaction mixture was transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain 44.4. (2.1 g, Yield: 38.77%). MS (ES):m/z 214.98 [M+H]⁺.

Synthesis of Compound 44.5

The compound was synthesized from compounds B.2 and 44.4 using GeneralProcedure A to obtain 44.5. (0.2 g, Yield: 41.15%), MS (ES): m/z 505.22[M+H]⁺.

Synthesis of Compound 44.6

The compound was synthesized from compound 44.5 using General ProcedureB to obtain 44.6. (0.110 g, Yield: 85.57%), MS (ES): m/z 325.13 [M+H]⁺.

Synthesis of Compound 44.7

The compound was synthesized from compound 44.6 using General ProcedureC to obtain 44.7. (0.090 g, Yield: 67.62%), MS (ES): m/z 393.15 [M+H]⁺.

Synthesis of Compound I-44

The compound was synthesized from compound 44.7 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-44 (0.025 g, Yield: 27.85%), MS (ES): m/z 392.70 [M+H]⁺ LCMS purity:100%, HPLC purity: 98.81%, ¹H NMR (DMSO-d₆, 400 MHz): 12.07 (s, 1H),11.35 (s, 1H), 9.07 (bs, 1H), 8.53-8.52 (d, J=5.6 Hz, 1H), 8.31-8.30 (d,J=6 Hz, 2H), 7.56-7.53 (m, 2H), 4.20 (bs, 1H), 2.86-2.85 (d, J=4.4 Hz,3H), 2.25 (bs, 1H), 1.08 (bs, 2H), 0.99 (bs, 2H), 0.97-0.92 (m, 4H).

Example 45:2-(2-cyano-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-7-(cyclopropane-carboxamido)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-45)

Synthesis of Compound 45.3

The compound was synthesized from compounds 45.1 and 45.2 using GeneralProcedure A to obtain 45.3. (0.650 g, Yield: 76.36%), MS (ES): m/z262.99 [M+H]⁺.

Synthesis of Compound 45.4

The compound was synthesized from compound 45.3 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 45.4. (0.5g, Yield: 84.78%). MS (ES): m/z 310.17 [M+H]⁺.

Synthesis of Compound 45.5

The compound was synthesized from Core A and compound 45.4 using GeneralProcedure A to obtain 45.5. (0.3 g, Yield: 61.35%), MS (ES): m/z 693.22[M+H]⁺.

Synthesis of Compound 45.6

The compound was synthesized from compound 45.5 using General ProcedureB to obtain 45.6. (0.150 g, Yield: 93.02%), MS (ES): m/z 373.14 [M+H]⁺.

Synthesis of Compound 45.7

The compound was synthesized from compound 45.6 using General ProcedureC to obtain 45.7. (0.110 g, Yield: 62.00%), MS (ES): m/z 441.16 [M+H]⁺.

Synthesis of Compound I-45

The compound was synthesized from compound 45.7 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-45 (0.030 g, Yield: 27.33%), MS (ES): m/z 440.42 [M+H]⁺ LCMS purity:96.41%, HPLC purity: 97.91%, ¹H NMR (DMSO-d₆, 400 MHz): 11.77 (s, 1H),11.22 (s, 1H), 8.43-8.42 (d, J=4 Hz, 1H), 8.35 (s, 1H), 8.32 (s, 1H),8.00 (s, 1H), 7.86-7.82 (m, 1H), 7.77-7.75 (d, J=7.6 Hz, 1H), 7.71-7.69(d, J=7.6 Hz, 1H), 7.52 (bs, 1H), 3.94 (s, 3H), 2.84-2.83 (d, J=4.4 Hz,3H), 2.21 (bs, 1H), 0.96-0.91 (m, 4H).

Example 46:7-(cyclopropanecarboxamido)-2-(2-(4-hydroxypiperidin-1-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-46)

Synthesis of Compound 46.2

To a solution of 1-bromo-2-iodobenzene (5.0 g, 17.66 mmol, 1.0 eq) in1,4-dioxane (80 mL) was added compound 46.1 (3.0 g, 21.19 mmol, 1.2 eq)and sodium tert-butoxide (3.3 g, 35.32 mmol, 2.0 eq). The reactionmixture was degassed for 10 min. under argon atmosphere, thentris(dibenzylideneacetone)dipalladium(0) (0.807 g, 0.88 mmol, 0.05 eq)and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.0 g, 1.76 mmol,0.1 eq) were added, again degassed for 5 min. The reaction was stirredat 120° C. for 4 h. After completion of reaction, reaction mixture wascooled to room temperature, transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by combiflash using 3% methanol in dichloromethane as eluant to obtain pure46.2. (1.2 g, Yield: 22.77%). MS (ES): m/z 299.03 [M+H]⁺.

Synthesis of Compound 46.3

The compound was synthesized from compounds B.2 and 46.2 using GeneralProcedure A to obtain 46.3. (0.250 g, Yield: 31.66%), MS (ES): m/z589.28 [M+H]⁺.

Synthesis of Compound 46.4

To a solution of compound 46.3 (0.250 g, 0.60 mmol, 1.0 eq), in methanol(3 mL) was added sodium hydroxide (0.120 g, 3.0 mmol, 5.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue. To this added water and acidified with 1N hydrochloricacid to adjust pH-6 at 10° C. Product was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 46.4. (0.2 g, Yield: 81.95%). MS (ES):m/z 575.26 [M+H]⁺.

Synthesis of Compound 46.5

The compound was synthesized from compound 46.4 and methylamine usingGeneral Procedure H to obtain 46.5. (0.180 g, Yield: 88%). MS (ES): m/z588.29 [M+H]⁺.

Synthesis of Compound 46.6

The compound was synthesized from compound 46.5 using General ProcedureB to obtain 46.6. (0.090 g, Yield: 80.86%), MS (ES): m/z 364.17 [M+H]⁺.

Synthesis of Compound 46.7

The compound was synthesized from compound 46.6 using General ProcedureC to obtain 46.7. (0.080 g, Yield: 74.87%), MS (ES): m/z 432.20 [M+H]⁺.

Synthesis of Compound I-46

To a solution of compound 46.7 (0.080 g, 0.18 mmol, 1.0 eq) in methanol(2 mL) was added sodium borohydride (0.027 g, 0.72 mmol, 4.0 eq)portionwise at 0° C. Reaction mixture was stirred at room temperaturefor 16 h. After completion of reaction, reaction mixture wasconcentrated under reduced pressure. To this was added water and productwas extracted with ethyl acetate. Organic layer was combined, washedwith brine solution, dried over sodium sulfate and concentrated underreduced pressure to obtain I-46 (0.038 g, Yield: 47.28%). MS (ES): m/z434.71 [M+H]⁺ LCMS purity: 95.29%, HPLC purity: 95.00%, ¹H NMR (DMSO-d₆,400 MHz): 12.40 (s, 1H), 11.28 (s, 1H), 8.33-8.32 (d, J=4.4 Hz, 1H),8.27 (s, 1H), 7.78-7.76 (s, J=7.2 Hz, 1H), 7.39-7.36 (t, J6.8 Hz, 1H),7.28 (bs, 2H), 7.18-7.15 (t, J7.6 Hz, 1H), 4.69 (s, 1H), 3.60 (bs, 1H),2.97 (bs, 2H), 2.86-2.85 (d, J=4 Hz, 3H), 2.61 (bs, 3H), 1.77 (bs, 2H),1.65 (bs, 2H), 1.05 (bs, 2H), 0.90 (bs, 2H).

Example 47:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-47)

Synthesis of Compound 47.3

To a solution of compounds 47.1 (1.0 g, 3.93 mmol, 1 eq) and 47.2 (0.391g, 4.71 mmol, 1.2 eq) in 1,4-dioxane (20 mL) was added cesium carbonate(2.5 g, 7.86 mmol, 2.0 eq) and degassed with argon for 15 min. Copperiodide (0.149 g, 0.78 mmol, 0.2 eq) and(1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (0.279 g, 1.96 mmol, 0.5eq) was added and reaction mixture again degassed with argon for 5 minfollowed by heating at 150° C. for 16 h. After completion of reaction,reaction mixture was cooled to room temperature, transferred into waterand product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and compound was eluted in1.2% methanol in dichloromethane to obtain pure 47.3 (0.4 g, Yield:39.66%). MS (ES): m/z 256.98 [M+H]⁺.

Synthesis of Compound 47.4

The compound was synthesized from compound 47.3 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 47.4. (0.3g, Yield: 63.36%). MS (ES): m/z 304.16 [M+H]⁺.

Synthesis of Compound 47.5

The compound was synthesized from Core A and compound 47.4 using GeneralProcedure A to obtain 47.5. (0.240 g, Yield: 49.51%), MS (ES): m/z687.21 [M+H]⁺.

Synthesis of Compound 47.6

The compound was synthesized from compound 47.5 using General ProcedureB to obtain 47.6. (0.120 g, Yield: 93.73%), MS (ES): m/z 367.13 [M+H]⁺.

Synthesis of Compound 47.7

The compound was synthesized from compound 47.6 using General ProcedureC to obtain 47.7. (0.090 g, Yield: 63.25%), MS (ES): m/z 435.15 [M+H]⁺.

Synthesis of Compound I-47

The compound was synthesized from compound 47.7 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-47 (0.027 g, Yield: 30.07%), MS (ES): m/z 434.66 [M+H]⁺ LCMS purity:96.76%, HPLC purity: 95.35%, ¹H NMR (DMSO-d₆, 400 MHz): 12.06 (s, 1H),11.31 (s, 1H), 8.97 (s, 1H), 8.33 (s, 1H), 8.05-8.01 (t, J=6.8 Hz, 1H),7.82-7.78 (t, J=7.2 Hz, 1H), 7.56 (s, 1H), 7.08-7.06 (d, J=7.6 Hz, 1H),6.83-6.81 (d, J=6.4 Hz, 1H), 2.84-2.83 (d, J=4.4 Hz, 3H), 2.40 (s, 3H),2.24 (bs, 1H), 0.97-0.92 (m, 4H).

Example 48:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-(1-methyl-1H-imidazol-4-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-48)

Synthesis of Compound 48.3

Argon was purged for 15 min through a stirred solution of compounds 48.1(1.0 g, 4.58 mmol, 1.0 eq), 48.2 (0.958 g, 5.95 mmol, 1.3 eq) andpotassium carbonate (1.5 g, 11.45 mmol, 2.5 eq) in 1,4-dioxane:water (20mL, 9:1). Bis(triphenylphosphine)palladium(II) dichloride (0.321 g, 0.45mmol, 0.1 eq) was added to it and further purging done for 10 min.Reaction was allowed to stir at 95° C. for 5 h. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain 48.3. (0.220 g, Yield: 18.87%). MS (ES): m/z 254.99[M+H]⁺.

Synthesis of Compound 48.4

The compound was synthesized from compounds B.2 and 48.3 using GeneralProcedure A to obtain 48.4. (0.180 g, Yield: 45.66%), MS (ES): m/z546.23 [M+H]⁺.

Synthesis of Compound 48.5

The compound was synthesized from compound 48.4 using General ProcedureB to obtain 48.5. (0.1 g, Yield: 82.96%), MS (ES): m/z 366.13[M+H]⁺.

Synthesis of Compound 48.6

The compound was synthesized from compound 48.5 using General ProcedureC to obtain 48.6. (0.080 g, Yield: 67.44%), MS (ES): m/z 434.16 [M+H]⁺.

Synthesis of Compound I-48

The compound was synthesized from compound 48.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-48 (0.025 g, Yield: 31.32%), MS (ES): m/z 433.25 [M+H]⁺ LCMS purity:95.71%, HPLC purity: 96.83%, ¹H NMR (DMSO-d₆, 400 MHz): 12.08 (s, 1H),11.39 (s, 1H), 8.46 (bs, 1H), 8.33 (s, 1H), 8.16 (bs, 1H), 8.09 (bs,1H), 7.84-7.82 (m, 2H), 7.53-7.47 (m, 2H), 3.82 (bs, 3H), 2.87 (bs, 3H),2.25 (bs, 1H), 1.03-1.01 (m, 4H).

Example 49:7-(cyclopropanecarboxamido)-2-(6-(1,4-dimethyl-1H-imidazol-2-yl)pyridin-2-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-49)

Synthesis of Compound 49.2

To a solution of compound 49.1 (5.0 g, 27.32 mmol, 1.0 eq) in ethanol(10 mL) was added hydrochloric acid (2.2 mL, 27.32 mmol, 1.0 eq). Thereaction mixture was stirred at room temperature for 15 min. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to obtain residue. To this added 30% aqueous ammonia solutionand was extracted with dichloromethane. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 7% ethyl acetate in hexane as eluant toobtain pure 49.2. (3.5 g, Yield: 64.04%). MS (ES): m/z 200.04 [M+H]⁺.

Synthesis of Compound 49.3

To a solution of compound 49.2 (3.5 g, 17.5 mmol, 1.0 eq) in ethanol (35mL) was added potassium carbonate (2.4 g, 17.5 mmol, 1.0 eq) at 0° C.followed by 1-bromopropan-2-one (2.5 g, 18.37 mmol, 1.05 eq) andreaction mixture was refluxed for 1 h. After completion of reaction;reaction mixture was concentrated under reduced pressure to obtainresidue which was transferred into ice cold water. Precipitated solidwas filtered, washed with water and dried under vacuum to obtain 49.3.(1.0 g, Yield: 24.01%). MS (ES): m/z 238.99 [M+H]⁺.

Synthesis of Compound 49.4

To a solution of compound 49.3 (1.0 g, 4.20 mmol, 1.0 eq) indimethylformamide (10 mL), was added sodium hydride (0.201 g, 8.4 mmol,2 eq) at 0° C. and stirred for 20 min. Methyl iodide (0.656 g, 4.62mmol, 1.1 eq) was added and reaction mixture was stirred at roomtemperature for 2 h. After completion of reaction, reaction mixture wastransferred into ice, stirred and extracted with diethyl ether. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bydistillation to obtain pure 49.4. (0.7 g, Yield: 66.11%). MS (ES): m/z253.00 [M+H]⁺.

Synthesis of Compound 49.5

The compound was synthesized from compounds B.2 and 49.4 using GeneralProcedure A to obtain 49.5. (0.250 g, Yield: 63.77%), MS (ES): m/z543.25 [M+H]⁺.

Synthesis of Compound 49.6

The compound was synthesized from compound 49.5 using General ProcedureB to obtain 49.6. (0.130 g, Yield: 77.86%), MS (ES): m/z 363.15 [M+H]⁺.

Synthesis of Compound 49.7

The compound was synthesized from compound 49.6 using General ProcedureC to obtain 49.7. (0.1 g, Yield: 64.76%), MS (ES): m/z 431.18 [M+H]⁺.

Synthesis of Compound I-49

The compound was synthesized from compound 49.7 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-49 (0.030 g, Yield: 30.07%), MS (ES): m/z 430.72 [M+H]⁺ LCMS purity:100%, HPLC purity: 96.66%, ¹H NMR (DMSO-d₆, 400 MHz): 12.12 (s, 1H),11.44 (s, 1H), 8.42 (bs, 1H), 8.32 (s, 1H), 8.09-8.07 (d, J=8 Hz, 1H),7.68 (s, 1H), 7.17 (s, 1H), 7.08 (bs, 1H), 6.85 (s, 1H), 4.18 (s, 3H),2.88-2.87 (d, J=4.4 Hz, 3H), 2.19 (s, 3H), 1.57 (bs, 1H), 0.99-0.97 (m,4H).

Example 50:7-(cyclopropanecarboxamido)-N-methyl-2-(3-(2-methyl-2H-tetrazol-5-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-50)

Synthesis of Compound 50.1

To a solution of 3-bromobenzonitrile (5.0 g, 5.49 mmol, 1.0 eq) intoluene (50 mL) was added dibutyltin chloride (3.3 g, 10.98 mmol, 2.0eq) and sodium azide (0.535 g, 8.23 mmol, 1.5 eq) The reaction wasstirred at room temperature for 4 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by combiflash using 3% methanol in dichloromethane as eluant to obtain pure50.1. (2.5 g, Yield. 40.44%). MS (ES): m-z 225.97 [M+H]⁺.

Synthesis of Compound 50.2

To a solution of compound 50.1 (1.0 g, 4.44 mmol, 1.0 eq) indimethylformamide (10 mL), was added sodium hydride (0.213 g, 8.88 mmol,2 eq) at 0° C. and stirred for 20 min. Methyl iodide (0.693 g, 4.88mmol, 1.1 eq) was added and reaction mixture was stirred at roomtemperature for 2 h. After completion of reaction, reaction mixture wastransferred into ice, stirred and extracted with diethyl ether. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bydistillation to obtain pure 50.2. (0.7 g, Yield: 65.89%). MS (ES): m/z239.98 [M+H]⁺.

Synthesis of Compound 50.3

The compound was synthesized from compound 50.2 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 50.3. (0.5g, Yield: 59.68%). MS (ES): m/z 287.16 [M+H]⁺.

Synthesis of Compound 50.4

The compound was synthesized from Core A and compound 50.3 using GeneralProcedure A to obtain 50.4. (0.280 g, Yield: 59.22%), MS (ES): m/z670.22 [M+H]⁺.

Synthesis of Compound 50.5

The compound was synthesized from compound 50.4 using General ProcedureB to obtain 50.5. (0.120 g, Yield: 82.16%), MS (ES): m/z 350.13 [M+H]⁺.

Synthesis of Compound 50.6

The compound was synthesized from compound 50.5 using General ProcedureC to obtain 50.6. (0.090 g, Yield: 62.77%), MS (ES): m/z 418.16 [M+H]⁺.

Synthesis of Compound I-50

The compound was synthesized from compound 50.6 and methylamine usingGeneral Procedure D. The material was further purified by columnchromatography eluting with 2.5% methanol in dichloromethane to obtainI-50 (0.026 g, Yield: 28.96%), MS (ES): m/z 417.60 [M+H]⁺ LCMS purity:95.02%, HPLC purity: 95.00%, ¹H NMR (DMSO-d₆, 400 MHz): 12.20 (s, 1H),11.24 (s, 1H), 8.55 (bs, 1H), 8.42-8.41 (d, J=4.4 Hz, 1H), 8.34 (s, 1H),8.12-8.11 (d, J=7.2 Hz, 2H), 7.77-7.73 (t, J=7.6 Hz, 1H), 7.47 (bs, 1H),4.49 (s, 3H), 2.87-2.86 (d, J=4.4 Hz, 3H), 2.21 (bs, 1H), 0.99-0.96 (m,4H).

Example 51:7-(cyclopropanecarboxamido)-2-(5-(dimethylcarbamoyl)-3-fluoropyridin-2-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-51)

Synthesis of Compound 51.2

The compound was synthesized from compound 51.1 and dimethylamine usingGeneral Procedure H to obtain 51.2 (0.7 g, Yield: 62.33%). MS (ES): m/z246.98 [M+H]⁺.

Synthesis of Compound 51.3

The compound was synthesized from compounds B.2 and 51.2 using GeneralProcedure A to obtain 51.3. (0.180 g, Yield: 46.35%), MS (ES): m/z538.22 [M+H]⁺.

Synthesis of Compound 51.4

The compound was synthesized from compound 51.3 using General ProcedureB to obtain 51.4. (0.110 g, Yield: 61.11%), MS (ES): m/z 358.22 [M+H]⁺.

Synthesis of Compound 51.5

The compound was synthesized from compound 51.4 using General ProcedureC to obtain 51.5. (0.085 g, Yield: 97.65%), MS (ES): m/z 426.15[M+H]⁺.

Synthesis of Compound 51.6

To a suspension of compound 51.5 (0.075 g, 0.17 mmol, 1.0 eq) in toluene(2 mL) was added tributyltin oxide (0.202 g, 0.34 mmol, 2.0 eq) andreaction mixture was heated at 100° C. for 48 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue which was dissolved in saturated sodium bicarbonatesolution and washed with hexane. Aqueous layer separated and acidifiedwith 1N hydrochloric acid to pH-5-6 and extracted with ethyl acetate.Organic layer was combined, dried over sodium sulfate and concentratedunder reduced pressure to obtain solid which was triturated with hexaneto obtain pure 51.6. (0.040 g, Yield: 55.15%), MS (ES): m/z 412.14[M+H]⁺.

Synthesis of Compound I-51

The compound was synthesized from compound 51.6 and methylamine usingGeneral Procedure H. The material was further purified by columnchromatography and the compound was eluted in 40% ethyl acetate inhexane to obtain I-51 (0.012 g, Yield: 77.54%). MS (ES): m/z 425.65[M+H]⁺ LCMS purity: 100%, HPLC purity: 95.71%, ¹H NMR (DMSO-d₆, 400MHz): 12.39 (s, 1H), 9.11 (s, 1H), 8.64 (bs, 1H), 8.27 (s, 1H), 7.70 (bs, 1H), 7.67 (b s, 1H), 7.17-7.15 (d, J=8 Hz, 1H), 4.38 (b s, 3H), 3.15(b s, 6H), 1.37 (b s, 1H), 0.92-0.90 (m, 4H).

Example 52:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-(2-methyl-2H-tetrazol-5-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-52)

Synthesis of Compound 52.2

To a solution of compound 52.1 (1.2 g, 4.93 mmol, 1.0 eq) indimethylformamide (12 mL), was added sodium hydride (0.236 g, 9.86 mmol,2 eq) at 0° C. and stirred for 20 min. Methyl iodide (0.770 g, 5.42mmol, 1.1 eq) was added and reaction mixture was stirred at roomtemperature for 2 h. After completion of reaction, reaction mixture wastransferred into ice, stirred and extracted with diethyl ether. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bydistillation to obtain pure 52.2. (0.8 g, Yield: 63.03%). MS (ES): m/z256.98 [M+H]⁺.

Synthesis of Compound 52.3

The compound was synthesized from compound 52.2 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 52.3.(0.640 g, Yield: 67.62%). MS (ES): m/z 305.15 [M+H]⁺.

Synthesis of Compound 52.4

The compound was synthesized from Core A and compound 52.3 using GeneralProcedure A to obtain 52.4. (0.260 g, Yield: 53.56%), MS (ES): m/z688.21 [M+H]⁺.

Synthesis of Compound 52.5

To a solution of compound 52.4 (0.260 g, 0.37 mmol, 1.0 eq), in methanol(5 mL) was added sodium hydroxide (0.074 g, 1.85 mmol, 5 eq). Thereaction was stirred at 60° C. for 6 h. After completion of reaction,reaction mixture was concentrated under reduced pressure to obtainresidue. To this added water and acidified with 1N hydrochloric acid toadjust pH-6-6.5 at 10° C. Product was extracted with dichloromethane.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography andcompound was eluted in 2.1% methanol in dichloromethane to obtain pure52.5. (0.160 g, Yield: 79.32%). MS (ES): m/z 534.20 [M+H]⁺.

Synthesis of Compound 52.6

The compound was synthesized from compound 52.5 and methylamine usingGeneral Procedure H to obtain 52.6. (0.140 g, Yield: 85.41%). MS (ES):m/z 547.23 [M+H]⁺.

Synthesis of Compound 52.7

The compound was synthesized from compound 52.6 using General ProcedureB to obtain 52.7. (0.093 g, Yield: 99.11%), MS (ES): m/z 367.14 [M+H]⁺.

Synthesis of Compound I-52

To a solution of compound cyclopropanecarboxylic acid (0.027 g, 0.32mmol, 1.0 eq), in N,N-dimethylformamide (2 mL) was added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.243 g, 0.64 mmol, 2.0 eq) and stirred atroom temperature for 15 min. To this added diisopropylethylamine (0.123g, 0.96 mmol, 3.0 eq) followed by addition of 52.7 (0.120 g, 0.32 mmol,1.0 eq), The reaction mixture was stirred at room temperature for 5 min.After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. Thematerial was further purified by column chromatography and the compoundwas eluted in 40% ethyl acetate in hexane to obtain I-52 (0.045 g,Yield: 31.62%). MS (ES): m/z 435.72 [M+H]⁺ LCMS purity: 100%, HPLCpurity: 98.65%, ¹H NMR (DMSO-d₆, 400 MHz): 12.13 (s, 1H), 11.33 (s, 1H),8.42 (bs, 1H), 8.35 (s, 1H), 8.17-8.13 (m, 2H), 7.56 (bs, 2H), 4.52 (bs,3H), 2.87 (bs, 3H), 1.24 (bs, 1H), 1.00-0.97 (m, 4H).

Example 53:7-(cyclopropanecarboxamido)-2-(5-(3,3-difluoroazetidine-1-carbonyl)pyridin-2-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-53)

Synthesis of Compound 53.2

The compound was synthesized from compound 53.1 and3,3-difluoroazetidine using General Procedure H to obtain 53.2 (0.5 g,Yield: 36.45%), MS (ES): m/z 276.97 [M+H]⁺.

Synthesis of Compound 53.3

The compound was synthesized from Core B and compound 53.2 using GeneralProcedure A to obtain 53.3. (0.120 g, Yield: 58.49%), MS (ES): m/z567.23 [M+H]⁺.

Synthesis of Compound 53.4

The compound was synthesized from compound 53.3 using General ProcedureB to obtain 53.4. (0.070 g, Yield: 85.55%), MS (ES): m/z 387.13 [M+H]⁺.

Synthesis of Compound I-53

The compound was synthesized from compound 53.4 andcyclopropanecarboxylic acid using General Procedure H. The material wasfurther purified by column chromatography and the compound was eluted in40% ethyl acetate in hexane to obtain I-53 (0.026 g, Yield: 31.58%).MS(ES): m/z 455.76 [M+H]⁺ LCMS purity: 96%, HPLC purity: 95.77%, ¹H NMR(DMSO-d₆, 400 MHz): 12.19 (s, 1H), 11.35 (s, 1H), 8.96 (bs, 1H), 8.39(s, 1H), 8.30 (s, 1H), 8.25-8.19 (m, 2H), 7.74 (s, 1H), 4.94 (bs, 2H),4.53 (bs, 2H), 2.85-2.84 (d, J=4.4 Hz, 3H), 2.26 (bs, 1H), 0.98-0.94 (m,4H).

Example 54:7-(cyclopropanecarboxamido)-N-methyl-2-(1-(5-methylthiazol-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-54)

Synthesis of Compound 54.3

To a solution of compounds 54.1 (1.0 g, 5.74 mmol, 1 eq) and 54.2 (1.2g, 6.88 mmol, 1.2 eq) in dimethylformamide (15 mL) was added potassiumcarbonate (1.5 g, 11.48 mmol, 2.0 eq) and degassed with argon for 15min. Copper iodide (0.262 g, 1.37 mmol, 0.2 eq) and(1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (0.326 g, 2.29 mmol, 0.4eq) was added and reaction mixture again degassed with argon for 5 minfollowed by heating at 100° C. for 16 h. After completion of reaction,reaction mixture was cooled to room temperature, transferred into waterand product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and compound was eluted in1.2% methanol in dichloromethane to obtain pure 52.3. (0.5 g, Yield:32.09%). MS (ES): m/z 270.95 [M+H]⁺.

Synthesis of Compound 54.4

The compound was synthesized from Core B and compound 54.3 using GeneralProcedure A to obtain 54.4. (0.110 g, Yield: 54.18%), MS (ES): m/z561.20 [M+H]⁺.

Synthesis of Compound 54.5

The compound was synthesized from compound 54.4 using General ProcedureB to obtain 54.5. (0.065 g, Yield: 87.09%), MS (ES): m/z 381.11 [M+H]⁺.

Synthesis of Compound I-54

The compound was synthesized from compound 54.5 using General ProcedureC to obtain I-54 (0.028 g, Yield: 36.54%). MS(ES): m/z 449.72 [M+H]⁺LCMS purity: 96.15%, HPLC purity: 95.00%, ¹H NMR (DMSO-d₆, 400 MHz):12.33 (s, 1H), 11.23 (s, 1H), 8.86-8.85 (bs, J=6 Hz, 1H), 8.43-8.41 (d,J=6.8 Hz, 1H), 8.35 (bs, 1H), 8.28 (bs, 1H), 8.59-8.55 (d, J=12.4 Hz,1H), 6.83-6.81 (t, J=7.2 Hz, 1H), 5.76 (s, 1H), 2.85-2.84 (d, J=4 Hz,3H), 2.32 (bs, 3H), 2.23 (bs, 1H), 0.99-0.96 (m, 4H).

Examples 55 and 56:(S)-7-(cyclopropanecarboxamido)-N-methyl-2-(2-oxo-1-(tetrahydro-2H-pyran-3-yl)-1,2-dihydropyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-55) and(R)-7-(cyclopropanecarboxamido)-N-methyl-2-(2-oxo-1-(tetrahydro-2H-pyran-3-yl)-1,2-dihydropyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-56)

Synthesis of Compounds I-55 and I-56

Enantiomers of compound I-43 were separated by on Shimadzu LC-20AP andUV detector. The column used was CHIRALPAK AD-H (250*21.0) mm, 5 micron,column flow was 18.0 ml/min. Mobile phase used was 0.1% Diethylamine inMethanol. The UV spectra were recorded at 240 nm Lambdamax.

Isocratic ratio was, as described below.

Mobile phase % Time (min) (0.1% DEA in MeOH) 0.01 100 25 100to provide pure fraction-1 and fraction-2.

Fraction-1 was concentrated under reduced pressure at 30° C. to affordpure I-55 (0.025 g). MS (ES): m/z 436.62 [M+H]⁺, LCMS purity: 97.01%,HPLC purity: 97.00%, CHIRAL HPLC purity: 97.54%, ¹H NMR (DMSO-d₆, 400MHz): 12.63 (s, 1H), 11.63 (s, 1H), 8.30-8.29 (d, J=5.6 Hz, 2H), 8.26(s, 1H), 8.03-8.02 (d, J=6 Hz, 1H), 7.45 (s, 1H), 6.57-6.53 (t, J=6.8Hz, 1H), 5.03 (bs, 1H), 3.89-3.84 (t, J=8.4 Hz, 2H), 3.59-3.54 (t, J=10Hz, 1H), 3.51-3.47 (t, J=9.6 Hz, 1H), 2.85-2.84 (d, J=4.4 Hz, 3H), 2.21(bs, 1H), 2.01 (bs, 2H), 1.79 (bs, 1H), 1.24 (bs, 1H), 0.97-0.93 (m,4H).

Fraction-2 was concentrated under reduced pressure at 30° C. to affordpure I-56 (0.026 g). MS (ES): m/z 436.67 [M+H]⁺, LCMS purity: 97.11%,HPLC purity: 96.75%, CHIRAL HPLC purity: 98.40%, ¹H NMR (DMSO-d₆, 400MHz): 12.63 (s, 1H), 11.15 (s, 1H), 8.30-8.29 (d, J=5.6 Hz, 2H), 8.26(s, 1H), 8.03-8.02 (d, J=6 Hz, 1H), 7.45 (s, 1H), 6.57-6.53 (t, J=6.8Hz, 1H), 5.03 (bs, 1H), 3.89-3.84 (t, J=8.4 Hz, 2H), 3.59-3.54 (t, J=10Hz, 1H), 3.51-3.47 (t, J=9.6 Hz, 1H), 2.85-2.84 (d, J=4.4 Hz, 3H), 2.21(bs, 1H), 2.03 (bs, 2H), 1.79 (bs, 1H), 1.24 (bs, 1H), 0.97-0.93 (m,4H).

Example 57:7-(cyclopropanecarboxamido)-2-(2-cyclopropoxy-4-(1-methyl-1H-imidazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-57)

Synthesis of Compound 57.1

To a solution of 4-bromo-2-fluoro-1-nitrobenzene (3.0 g, 13.63 mmol, 1.0eq) in tetrahydrofuran (30 mL), was added sodium hydride (0.654 g, 27.26mmol, 2 eq) at 0° C. and stirred for 20 min. Cyclopropanol (0.869 g,14.99 mmol, 1.1 eq) was added and reaction mixture was stirred at roomtemperature for 2 h. After completion of reaction, reaction mixture wastransferred into ice, stirred and extracted with diethyl ether. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bydistillation to obtain pure 57.1. (2.7 g, Yield: 76.72%). MS (ES): m/z257.97 [M+H]⁺.

Synthesis of Compound 57.2

The compound was synthesized from compound 57.1 using General ProcedureF, using 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl insteadof 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to obtain 57.2. (1.3g, Yield: 40.72%). MS (ES): m/z 306.15 [M+H]⁺.

Synthesis of Compound 57.3

Argon was purged for 15 min through a stirred solution of compound 57.2(1.3 g, 4.26 mmol, 1.0 eq) and 2-bromo-1-methyl-1H-imidazole (0.891 g,5.53 mmol, 1.3 eq) in dimethylformamide (10 mL).Bis(triphenylphosphine)palladium(II) dichloride (0.298 g, 0.42 mmol, 0.1eq) was added to it and further purging done for 10 min. Reaction wasallowed to stir at 100° C. for 5 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain 57.3. (0.7 g, Yield: 63.37%). MS (ES): m/z 260.09[M+H]⁺.

Synthesis of Compound 57.4

To a solution of compound 57.3 (0.7 g, 2.70 mmol, 1.0 eq) in methanol(14 ml), palladium on charcoal (0.36 g) was added. Hydrogen was purgedthrough reaction mixture for 4 h at room temperature. After completionof reaction, reaction mixture was filtered through Celite-bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 57.4. (0.6 g, Yield: 96.92%). MS (ES): m/z230.12 [M+H]⁺.

Synthesis of Compound 57.5

To the compound 57.4 (0.6 g, 2.60 mmol, 1.0 eq) was added 30%hydrobromic acid (1.2 mL) dropwise at 0° C. Sodium nitrite (0.358 g, 5.2mmol, 2.0 eq) and acetone (4.8 mL) were added to this reaction mixtureand stirred for 2 min. Then copper(I) bromide (0.743 g, 5.2 mmol, 2.0eq) was added and reaction mixture was stirred for 15 min. Aftercompletion of reaction, reaction mixture was transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain 57.5. (0.3 g, Yield: 39.10%). MS (ES):m/z 293.02 [M+H]⁺.

Synthesis of Compound 57.6

The compound was synthesized from compounds B.2 and 57.5 using GeneralProcedure A to obtain 57.6. (0.180 g, Yield: 51.22%), MS (ES): m/z584.26 [M+H]⁺.

Synthesis of Compound 57.7

To a solution of compound 57.6 (0.180 g, 0.30 mmol, 1.0 eq), in methanol(2 mL) was added sodium hydroxide (0.06 g, 1.5 mmol, 5.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue. To this added water and acidified with 1N hydrochloricacid to adjust pH-6 at 10° C. Product was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 57.7. (0.140 g, Yield: 79.69%). MS (ES):m/z 570.25 [M+H]⁺.

Synthesis of Compound 57.8

The compound was synthesized from compound 57.7 and methylamine usingGeneral Procedure H to obtain 57.8. (0.120 g, Yield: 83.80%). MS (ES):m/z 583.28 [M+H]⁺.

Synthesis of Compound 57.9

The compound was synthesized from compound 57.8 using General ProcedureB to obtain 57.9. (0.070 g, Yield: 84.46%), MS (ES): m/z 403.18 [M+H]⁺.

Synthesis of Compound I-57

The compound was synthesized from compound 57.9 using General ProcedureC to obtain I-57 (0.028 g, Yield: 34.21%). MS (ES): m/z 471.30 [M+H]⁺LCMS purity: 95.37%, HPLC purity: 96.11%, ¹H NMR (DMSO-d₆, 400 MHz):12.27 (s, 1H), 11.54 (s, 1H), 8.71-8.69 (d, J=8 Hz, 2H), 8.55 (s, 1H),7.83 (s, 1H), 7.63 (s, 1H), 6.94 (s, 2H), 5.77 (s, 1H), 4.6 (bs, 1H),3.96 (s, 3H), 2.62 (s, 3H), 2.21 (bs, 1H), 1.09-1.00 (m, 4H), 0.86-0.83(m, 4H).

Example 58:7-(cyclopropanecarboxamido)-2-(2-fluoro-4-(1-methyl-1H-imidazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-58)

Synthesis of Compound 58.3

Argon was purged for 15 min through a stirred solution of compounds 58.1(2.0 g, 6.66 mmol, 1.0 eq) and 58.2 (3.2 g, 8.65 mmol, 1.3 eq) indimethylformamide (50 mL). Bis(triphenylphosphine)palladium(II)dichloride (0.466 g, 0.66 mmol, 0.1 eq) was added to it and furtherpurging done for 10 min. Reaction was allowed to stir at 60° C. for 5 h.After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain 58.3. (0.160 g, Yield:10.44%). MS (ES): m/z 254.99 [M+H]⁺.

Synthesis of Compound 58.4

The compound was synthesized from compounds B.2 and 58.3 using GeneralProcedure A to obtain 58.4. (0.180 g, Yield: 54.80%), MS (ES): m/z546.23 [M+H]⁺.

Synthesis of Compound 58.5

To a solution of compound 58.4 (0.180 g, 0.33 mmol, 1.0 eq), in methanol(2 mL) was added sodium hydroxide (0.066 g, 1.65 mmol, 5.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue. To this added water and acidified with 1N hydrochloricacid to adjust pH-6 at 10° C. Product was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 58.5. (0.120 g, Yield: 68.43%). MS (ES):m/z 532.21 [M+H]⁺.

Synthesis of Compound 58.6

The compound was synthesized from compound 58.5 and methylamine usingGeneral Procedure H to obtain 58.6. (0.1 g, Yield: 81.34%), MS (ES): m/z545.24 [M+H]⁺.

Synthesis of Compound 58.7

The compound was synthesized from compound 58.6 using General ProcedureB to obtain 58.7. (0.050 g, Yield: 74.73%), MS (ES): m/z 365.15 [M+H]⁺.

Synthesis of Compound I-58

The compound was synthesized from compound 58.7 andcyclopropanecarboxylic acid using General Procedure H. The material wasfurther purified by column chromatography and the compound was eluted in40% ethyl acetate in hexane to obtain 1-58 (0.030 g, Yield: 50.56%), MS(ES): m/z 433.72 [M+H]⁺ LCMS purity: 99.02%, HPLC purity: 96.75%, ¹H NMR(DMSO-d₆, 400 MHz): 12.16 (s, 1H), 11.35 (s, 1H), 9.06 (bs, 1H), 8.42(s, 1H), 8.40 (s, 1H), 8.12-8.08 (t, J=8 Hz, 1H), 7.81-7.76 (t, J=13.2Hz, 2H), 7.55 (s, 1H), 7.40 (s, 1H), 3.88 (s, 3H), 2.87-2.86 (d, J=4.4Hz, 3H), 1.35 (bs, 1H), 1.00-0.95 (m, 4H).

Example 59:7-(cyclopropanecarboxamido)-2-(2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-59)

Synthesis of Compound 59.2

To a solution of compound 59.1 (1.0 g, 5.05 mmol, 1.0 eq) inN,N-dimethylformamide (10 mL), was added potassium carbonate (1.3 g,10.1 mmol, 2.0 eq) at 0° C. and stirred for 15 min. To this added methyliodide (1.4 g, 10.1 mmol, 2 eq) dropwise and reaction mixture wasstirred at 60° C. for 2 h. After completion of reaction, reactionmixture was transferred in ice-water and precipitated product wasfiltered and dried to obtain 59.2 (0.9 g, Yield: 84.05%). MS (ES): m/z212.96 [M+H]⁺.

Synthesis of Compound 59.3

To a solution of compound 59.2 (0.9 g, 4.26 mmol, 1.0 eq) in dimethylsulfoxide (10 mL), was added potassium carbonate (0.293 g, 2.13 mmol,0.5 eq) and hydrogen peroxide (0.159 g, 4.68 mmol, 1.1 eq) dropwise andreaction mixture was stirred at 60° C. for 2 h. After completion ofreaction, reaction mixture was transferred in ice-water and precipitatedproduct was filtered and dried to obtain 59.3. (0.85 g, Yield: 87.05%).MS (ES): m/z 230.97 [M+H]⁺.

Synthesis of Compound 59.4

To a suspension of sodium azide (0.719 g, 11.07 mmol, 3.0 eq) inacetonitrile (10 mL) was added silicon tetrachloride (0.689 g, 4.05mmol, 1.1 eq) and reaction mixture was stirred. To this added compound59.3 (0.850 g, 3.69 mmol, 1.0 eq) and reaction mixture was stirred at75° C. for 16 h. Reaction mixture was cooled to room temperature andwater was added. A solid precipitated, which was filtered and dried toobtain 59.4. (0.7 g, Yield: 74.28%). MS (ES): m/z 255.98 [M+H]⁺.

Synthesis of Compound 59.5

To a solution of 59.4 (0.7 g, 2.74 mmol, 1.0 eq) inN,N-dimethylformamide (7 mL) was added potassium carbonate (1.1 g, 8.22mmol, 3.0 eq) at 0° C. To this added dropwise methyl iodide (0.505 g,3.56 mmol, 1.3 eq). Reaction mixture was stirred at room temperature for24 h. After completion of reaction, reaction mixture was transferredinto water and extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by column chromatography and the depicted regioisomer waseluted in 10% ethyl acetate in hexane to obtain pure 59.5 (0.250 g,Yield: 33.85%). MS (ES): m/z 269.99 [M+H]⁺.

Synthesis of Compound 59.6

The compound was synthesized from compounds B.2 and 59.35 using GeneralProcedure A to obtain 59.6. (0.180 g, Yield: 53.43%), MS (ES): m/z560.24 [M+H]⁺.

Synthesis of Compound 59.7

To a solution of 59.6 (0.180 g, 0.33 mmol, 1.0 eq), in methanol (2 mL)was added sodium hydroxide (0.066 g, 1.65 mmol, 5.0 eq). The reactionmixture was stirred at 60° C. for 1 h. After completion of reaction,reaction mixture was concentrated under reduced pressure to obtainresidue. To this added water and acidified with 1N hydrochloric acid toadjust pH-6 at 10° C. Product was extracted with dichloromethane.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography andcompound was eluted in 2.1% methanol in dichloromethane to obtain pure59.7. (0.110 g, Yield: 62.68%). MS (ES): m/z 546.22 [M+H]⁺.

Synthesis of Compound 59.8

The compound was synthesized from compound 59.7 and methylamine usingGeneral Procedure H to obtain 59.8. (0.1 g, Yield: 88.79%). MS (ES): m/z559.25 [M+H]⁺.

Synthesis of Compound 59.9

The compound was synthesized from compound 59.8 using General ProcedureB to obtain 59.9. (0.060 g, Yield: 88.58%), MS (ES): m/z 379.16 [M+H]⁺.

Synthesis of Compound I-59

The compound was synthesized from compound 59.9 using General ProcedureC to obtain I-59 (0.030 g, Yield: 42.38%), MS (ES): m/z 447.46 [M+H]⁺LCMS purity: 100%, HPLC purity: 95.77%, ¹H NMR (DMSO-d₆, 400 MHz): 12.30(s, 1H), 11.30 (s, 1H), 8.61 (s, 1H), 8.34-8.33 (d, J=4 Hz, 1H),8.04-8.02 (d, J=7.6 Hz, 1H), 7.81-7.87-7.85 (d, J=7.6 Hz, 1H), 7.38-7.34(t, J=7.6 Hz, 1H), 7.07-7.06 (bs, 1H), 3.98 (s, 3H), 3.64 (s, 3H),2.85-0.84 (d, J=4.4 Hz, 3H), 2.25 (bs, 1H), 0.97-0.92 (m, 4H).

Example 60:7-(cyclopropanecarboxamido)-2-(2-methoxy-4-(thiazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-60)

Synthesis of Compound 60.3

Argon was purged for 15 min through a stirred solution of compounds 60.1(2.0 g, 9.90 mmol, 1.0 eq) and 60.2 (4.8 g, 12.87 mmol, 1.3 eq) indimethylformamide (30 mL). Bis(triphenylphosphine)palladium(II)dichloride (0.694 g, 0.99 mmol, 0.1 eq) was added to it and furtherpurging done for 10 min. Reaction was allowed to stir at 60° C. for 5 h.After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain 60.3. (1.1 g, Yield:53.88%). MS (ES): m/z 207.05 [M+H]⁺.

Synthesis of Compound 60.4

To a solution of compound 60.3 (1.0 g, 4.85 mmol, 1.0 eq) inacetonitrile (15 mL) was added tert-butyl nitrite (0.549 g, 5.33 mmol,1.1 eq) and copper(II) bromide (2.1 g, 9.7 mmol, 2.0 eq). Reaction wasallowed to stir at 90° C. for 5 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure. This was further purified by column chromatography andcompound was eluted in 40% ethyl acetate in hexane to obtain 60.4. (0.4g, Yield: 30.54%). MS (ES): m/z 270.95 [M+H]⁺.

Synthesis of Compound 60.5

The compound was synthesized from compounds B.2 and 60.4 using GeneralProcedure A to obtain 60.5. (0.210 g, Yield: 62.21%), MS (ES): m/z561.19 [M+H]⁺.

Synthesis of Compound 60.6

To a solution of compound 60.5 (0.210 g, 0.37 mmol, 1.0 eq), in methanol(2 mL) was added sodium hydroxide (0.074 g, 1.85 mmol, 5.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue. To this added water and acidified with 1N hydrochloricacid to adjust pH-6 at 10° C. Product was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 60.6. (0.180 g, Yield: 87.91%). MS (ES):m/z 547.18 [M+H]⁺.

Synthesis of Compound 60.7

The compound was synthesized from compound 60.6 and methylamine usingGeneral Procedure H to obtain 60.7. (0.140 g, Yield: 75.97%). MS (ES):m/z 560.21 [M+H]⁺.

Synthesis of Compound 60.8

The compound was synthesized from compound 60.7 using General ProcedureB to obtain 60.8. (0.090 g, Yield: 94.82%), MS (ES): m/z 380.11 [M+H]⁺.

Synthesis of Compound I-60

The compound was synthesized from compound 60.8 andcyclopropanecarboxylic acid using General Procedure H. The material wasfurther purified by column chromatography and the compound was eluted in40% ethyl acetate in hexane to obtain I-60 (0.032 g, Yield: 30.15%), MS(ES): m/z 448.8 [M+H]⁺ LCMS purity: 100%, HPLC purity: 98.43%, ¹H NMR(DMSO-d₆, 400 MHz): 12.55 (s, 1H), 11.33 (s, 1H), 8.34 (bs, 1H), 8.29(s, 1H), 8.14-8.12 (d, J=8 Hz, 1H), 8.00 (bs, 1H), 7.89 (bs, 1H), 7.76(bs, 1H), 7.69-7.67 (d, J=8 Hz, 1H), 7.52 (bs, 1H), 4.12 (s, 3H), 2.87(bs, 3H), 2.26 (bs, 1H), 1.03-0.97 (m, 4H).

Example 61:2-(4-(1,4-dioxan-2-yl)-2-methoxyphenyl)-7-(cyclopropanecarboxamido)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-61)

Synthesis of Compound 61.2

To a solution of compound 61.1 (5.0 g, 32.89 mmol, 1.0 eq) in 1,4dioxane (70 mL) was added tripotassium phosphate (6.9 g, 32.89 mmol, 1.0eq), triphenylphosphine (0.083 g, 0.32 mmol, 0.01 eq) and nickel(II)acetylacetonate (0.081 g, 0.32 mmol, 0.01 eq). After stirring for a 15min, t-butyl hydroperoxide (3.5 g, 39.46 mmol, 1.2 eq) was The reactionmixture was stirred at 100° C. for 16 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 15% ethyl acetate inhexane to obtain 61.2. (2.1 g, Yield: 32.86%). MS (ES): m/z 195.10[M+H]⁺.

Synthesis of Compound 61.3

To a solution of compound 61.2 (2.1 g, 10.82 mmol, 1.0 eq) in1,2-dichloroethane (30 mL) was added N-bromosuccinimide (2.8 g, 16.23mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at sametemperature for 30 min. After completion of reaction, reaction mixturewas transferred into ice cold water and product was extracted with ethylacetate. Organic layer was combined and dried over sodium sulfate andconcentrated under reduced pressure to obtain 61.3. (0.860 g, Yield:29.12%). MS (ES): m/z 273.01 [M+H]⁺.

Synthesis of Compound 61.4

The compound was synthesized from compounds B.2 and 61.3 using GeneralProcedure A to obtain 61.4. (0.320 g, Yield: 42.86%), MS (ES): m/z564.25 [M+H]⁺.

Synthesis of Compound 61.5

To a solution of compound 61.4 (0.320 g, 0.56 mmol, 1.0 eq), in methanol(4 mL) was added sodium hydroxide (0.112 g, 2.8 mmol, 5.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue. To this added water and acidified with 1N hydrochloricacid to adjust pH-6 at 10° C. Product was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 61.5. (0.280 g, Yield: 89.73%). MS (ES):m/z 550.23 [M+H]⁺.

Synthesis of Compound 61.6

The compound was synthesized from compound 61.5 and methylamine usingGeneral Procedure H to obtain 61.6. (0.250 g, Yield: 87.22%), MS (ES):m/z 563.24 [M+H]⁺.

Synthesis of Compound 61.7

To a solution of 61.6 (0.250 g, 0.44 mmol, 1.0 eq) in methanol (5 ml),10% palladium hydroxide charcoal (0.2 g) was added. Hydrogen was purgedthrough reaction mixture for 6 h at room temperature. After completionof reaction, reaction mixture was filtered through Celite-bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 61.7. (0.080 g, Yield: 47.08%). MS (ES): m/z451.19 [M+H]⁺.

Synthesis of Compound I-61

The compound was synthesized from compound 61.7 andcyclopropanecarboxylic acid using General Procedure H. The material wasfurther purified by column chromatography and the compound was eluted in40% ethyl acetate in hexane to obtain 1-61 (0.025 g, Yield: 35.37%). MS(ES): m/z 451.62 [M+H]⁺ LCMS purity: 100%, HPLC purity: 100%, ¹H NMR(DMSO-d₆, 400 MHz): 11.47 (s, 1H), 11.18 (s, 1H), 8.37 (bs, 1H), 8.34(bs, 1H), 7.49-7.47 (d, J=8 Hz, 1H), 7.17 (bs, 1H), 7.10-7.08 (d, J=8.4Hz, 1H), 7.00 (bs, 1H), 4.75-4.72 (d, J=10.4 Hz, 1H), 3.85 (s, 3H),3.71-3.68 (d, J=10 Hz, 3H), 3.55-3.50 (s, 2H), 2.87-2.85 (d, J=4 Hz,3H), 2.19 (s, 1H), 1.25 (bs, 1H), 1.00-0.92 (bs, 4H).

Example 62:7-(cyclopropanecarboxamido)-2-(2-fluoro-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-62)

Synthesis of Compound 62.3

To a solution of compound 62.1 (4.0 g, 16.87 mmol, 1.0 eq) in pyridine(20 mL) was added compound 62.2 (1.7 g, 16.87 mmol, 1.0 eq). Thereaction mixture was stirred at room temperature for 1 h. Aftercompletion of reaction, reaction mixture was transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by trituration using hexane to obtain 62.3. (4.0 g, Yield:77.56%). MS (ES): m/z 306.96 [M+H]⁺.

Synthesis of Compound 62.4

A solution of compound 62.3 (4.0 g, 13.07 mmol, 1.0 eq) in 50% aqueoussodium bicarbonate (120 mL) was refluxed at 100° C. for 2 h. Aftercompletion of reaction, reaction mixture was filtered. Filtrate wascooled to room temperature and acidified with dilute hydrochloric acid.Filtrate was extracted with ethyl acetate. Organic layer was combined,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 12% ethyl acetate in hexane toobtain pure 62.4. (2.0 g, Yield: 53.13%). MS (ES): m/z 288.95 [M+H]⁺.

Synthesis of Compound 62.5

A solution of compound 62.4 (2.0 g, 6.94 mmol, 1.0 eq) in 69% aqueousnitric acid (10 mL) and water (30 mL) was warmed gently. The reactionwas completed by slowly increasing temperature and refluxed for 1 h.After completion of reaction, reaction mixture was cooled to 0° C.,basified by ageous sodium hydroxide solution and extracted withdichloromethane. Organic layer was combined, dried over sodium sulfateand concentrated under reduced pressure to obtain crude material. Thiswas further purified by column chromatography and compound was eluted in20% ethyl acetate in hexane to obtain pure 62.5. (0.7 g, Yield: 39.38%),MS (ES): m/z 255.98 [M+H]⁺.

Synthesis of Compound 62.6

The compound was synthesized from compounds B.2 and 62.5 using GeneralProcedure A to obtain 62.6. (0.210 g, Yield: 53.18%), MS (ES): m/z547.22 [M+H]⁺.

Synthesis of Compound 62.7

To a solution of compound 62.6 (0.210 g, 0.38 mmol, 1.0 eq), in methanol(2 mL) was added sodium hydroxide (0.076 g, 1.9 mmol, 5.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue. To this added water and acidified with 1N hydrochloricacid to adjust pH-6 at 10° C. Product was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 62.7. (0.160 g, Yield: 78.20%). MS (ES):m/z 534.21 [M+H]⁺.

Synthesis of Compound 62.8

The compound was synthesized from compound 62.7 and methylamine usingGeneral Procedure H to obtain 62.8. (0.130 g, Yield: 79.31%), MS (ES):m/z 546.24 [M+H]⁺.

Synthesis of Compound 62.9

The compound was synthesized from compound 62.8 using General ProcedureB to obtain 62.9. (0.060 g, Yield: 68.92%), MS (ES): m/z 366.14 [M+H]⁺.

Synthesis of Compound I-62

The compound was synthesized from compound 62.9 andcyclopropanecarboxylic acid using General Procedure H. The material wasfurther purified by column chromatography and the compound was eluted in40% ethyl acetate in hexane to obtain I-62 (0.027 g, Yield: 38.35%), MS(ES): m/z 434.6 [M+H]⁺ LCMS purity: 97.82%, HPLC purity: 95.77%, ¹H NMR(DMSO-d₆, 400 MHz): 12.22 (s, 1H), 11.37 (s, 1H), 8.66 (bs, 1H), 8.43(bs, 1H), 8.35 (s, 1H), 8.19-8.15 (t, J7.6 Hz, 1H), 7.89-7.80 (m, 2H),7.58 (bs, 1H), 3.86 (s, 3H), 2.87-2.86 (d, J=4 Hz, 3H), 1.56 (bs, 1H),1.00-0.97 (bs, 4H).

Example 63:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-(2H-1,2,3-triazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-63)

Synthesis of Compound 63.1

To a solution of 1,2-difluoro-4-nitrobenzene (5.0 g, 31.25 mmol, 1.0 eq)and 1H-1,2,3-triazole (4.3 g, 62.5 mmol, 2.0 eq) in dimethyl sulphoxide(60 mL) was added potassium carbonate (8.6 g, 11.56 mmol, 2.0 eq) andreaction mixture heated at 80° C. for 4 h. After completion of reaction,reaction mixture was transferred into ice cold water and product wasextracted with ethyl acetate. Organic layer was combined and dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography andcompound was eluted in 25% ethyl acetate in hexane to obtain pure 63.1.(1.5 g, Yield: 22.93%). MS (ES): m/z 209.04 [M+H]⁺.

Synthesis of Compound 63.2

To a solution of compound 63.1 (1.5 g, 7.21 mmol, 1.0 eq) in methanol(25 ml), palladium on charcoal (0.7 g) was added. Hydrogen was purgedthrough reaction mixture for 4 h at room temperature. After completionof reaction, reaction mixture was filtered through Celite-bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 63.2. (1.25 g, 97.36%). MS (ES): m/z 179.07[M+H]⁺.

Synthesis of Compound 63.3

To a solution of compound 63.2 (0.9 g, 5.02 mmol, 1.0 eq) inacetonitrile (15 mL) was added N-bromosuccinimide (1.3 g, 7.53 mmol, 1.5eq) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Aftercompletion of reaction, reaction mixture was transferred into ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined and dried over sodium sulfate and concentrated under reducedpressure to obtain 63.3. (0.650 g, Yield: 50.06%). MS (ES): m/z 257.97[M+H]⁺.

Synthesis of Compound 63.4

To a cooled solution of compound 63.3 (0.650 g, 2.52 mmol, 1.0 eq) intetrahydrofuran (7 mL) was added trifluoroacetic acid (0.6 mL) at 0° C.Then added 2N hydrochloric acid (6.5 mL) and stirred reaction mixturefor 5 min. Then added solution of sodium nitrite (0.173 g, 2.52 mmol,1.0 eq) in 5 mL water followed by 3% hydrogen peroxide (6.5 mL) andreaction mixture was stirred at 0° C. for 30 min and then at roomtemperature for 1 h. After completion of reaction, reaction mixture wastransferred into ice cold water and product was extracted with ethylacetate. Organic layer was combined and dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and the compound was eluted in7% ethyl acetate in hexane to obtain 63.4. (0.3 g, Yield: 49.02%). MS(ES): m/z 242.96 [M+H]⁺.

Synthesis of Compound 63.5

The compound was synthesized from compounds B.2 and 63.4 using GeneralProcedure A to obtain 63.5. (0.220 g, Yield: 57.18%), MS (ES): m/z533.21 [M+H]⁺.

Synthesis of Compound 63.6

To a solution of compound 63.5 (0.220 g, 0.40 mmol, 1.0 eq), in methanol(2 mL) was added sodium hydroxide (0.080 g, 2.0 mmol, 5.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue. To this added water and acidified with 1N hydrochloricacid to adjust pH-6 at 10° C. Product was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 63.6. (0.160 g, Yield: 74.69%). MS (ES):m/z 519.19 [M+H]⁺.

Synthesis of Compound 63.7

The compound was synthesized from compound 63.6 and methylamine usingGeneral Procedure H to obtain 63.7. (0.140 g, Yield: 85.35%), MS (ES):m/z 532.22[M+H]⁺.

Synthesis of Compound 63.8

The compound was synthesized from compound 63.7 using General ProcedureB to obtain 63.8. (0.070 g, Yield: 75.65%), MS (ES): m/z 352.01 [M+H]⁺.

Synthesis of Compound I-63

The compound was synthesized from compound 63.8 using General ProcedureC to obtain I-63 (0.030 g, Yield: 37.14%), MS (ES): m/z 420.75 [M+H]⁺LCMS purity: 100%, HPLC purity: 99.49%, ¹H NMR (DMSO-d₆, 400 MHz): 11.78(s, 1H), 11.03 (s, 1H), 8.35-8.34 (d, J=5.2 Hz, 2H), 8.26 (bs, 3H),8.06-8.04 (m, 1H), 7.74-7.69 (t, J=10.4 Hz, 1H), 7.44 (s, 1H), 2.85-2.84(d, J=4.4 Hz, 3H), 2.21 (bs, 1H), 0.96-0.91 (m, 4H).

Example 64:7-(cyclopropanecarboxamido)-2-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-64)

Synthesis of Compound 64.2

To a solution of compound 64.1 (1.0 g, 7.57 mmol, 1.0 eq) inN,N-dimethylformamide (15 mL), was added trimethylsilyl azide (1.7 g,15.14 mmol, 2.0 eq), copper(I) iodide (1.5 g, 7.94 mmol, 1.05 eq) anddiisopropylethylamine (2.9 g, 22.71 mmol, 3.0 eq). The reaction mixturewas stirred at 60° C. for 10 h. After completion of reaction, reactionmixture was transferred into water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtain64.2 (0.74 g, Yield: 55.82%). MS (ES): m/z 176.08 [M+H]⁺.

Synthesis of Compound 64.3

To a solution of compound 64.2 (2.2 g, 12.57 mmol, 1.0 eq) inN,N-dimethylformamide (25 mL), was added potassium carbonate (3.4 g,25.14 mmol, 2.0 eq) at 0° C. and stirred for 15 min. To this addedmethyl iodide (3.5 g, 25.14 mmol, 2 eq) dropwise and reaction mixturewas stirred at 60° C. for 2 h. After completion of reaction, reactionmixture was transferred in ice-water and precipitated product wasfiltered and dried to obtain 64.3 (0.700 g, Yield: 29.46%). MS (ES): m/z190.09 [M+H]⁺.

Synthesis of Compound 64.4

To a solution of compound 64.3 (0.550 g, 2.91 mmol, 1.0 eq) in1,2-dichloroethane (6 mL) was added N-bromosuccinimide (0.776 g, 4.36mmol, 1.5 eq). The reaction mixture was stirred at room temperature for20 min. After completion of reaction, reaction mixture was transferredto ice cold water and product was extracted with ethyl acetate. Organiclayer was combined, washed with brine solution, dried over sodiumsulfate and concentrated under reduced pressure to obtain 64.4. (0.25 g,Yield: 32.08%). MS (ES): m/z 269.00 [M+H]⁺.

Synthesis of Compound 64.5

The compound was synthesized from Core B and compound 64.4 using GeneralProcedure A to obtain 64.5. (0.120 g, Yield: 44.57%), MS (ES): m/z558.26 [M+H]⁺.

Synthesis of Compound 64.6

The compound was synthesized from compound 64.5 using General ProcedureB to obtain 64.6. (0.060 g, Yield: 73.88%), MS (ES): m/z 378.16 [M+H]⁺.

Synthesis of Compound I-64

The compound was synthesized from compound 64.6 using General ProcedureC to obtain I-64 (0.025 g, Yield: 35.30%), MS (ES): m/z 446.76 [M+H]⁺LCMS purity: 95.2%, HPLC purity: 95.4%, ¹H NMR (DMSO-d₆, 400 MHz): 12.21(s, 1H), 11.14 (s, 1H), 8.29 (s, 1H), 7.77 (s, 1H), 7.65-7.63 (d, J=8Hz, 1H), 7.52 (bs, 1H), 7.31 (s, 1H), 7.09 (bs, 2H), 3.98 (s, 3H), 3.89(s, 3H), 2.32 (bs, 1H), 1.25 (bs, 4H).

Example 65:7-(cyclopropanecarboxamido)-2-(2-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-65)

Synthesis of Compound 65.2

To a solution of compound 65.1 (2.0 g, 10.52 mmol, 1.0 eq) in 12Mhydrochloric acid in water (20 mL) was added ethanol (10 mL) and cooledto −20° C. and stirred for 10 min. Then added sodium nitrite (5 mL inwater) (1.0 g, 14.72 mmol, 1.4 eq) dropwise and stirred for 30 min atsame temperature. Then added tin(II) chloride (3.9 g, 21.04 mmol, 2.0eq). The reaction mixture was stirred at same temperature for 30 min.After completion of reaction, solid material was filtered and wash withwater dried under vaccum to obtain 65.2. (0.4 g, Yield: 18.54%). MS(ES): m/z 204.97 [M+H]⁺.

Synthesis of Compound 65.4

To a solution of compound 65.2 (1.0 g, 4.87 mmol, 1.0 eq) in pyridine(10 mL) was added compound 65.3 (0.555 g, 4.87 mmol, 1.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified bytrituration using hexane to obtain 65.4. (0.5 g, Yield: 37.40%). MS(ES): m/z 273.99 [M+H]⁺.

Synthesis of Compound 65.5

To a solution of compound 65.4 (0.5 g, 1.83 mmol, 1.0 eq) in pyridine (5mL) was added pyridine hydrochloride (0.105 g, 0.91 mmol, 1.0 eq). Thereaction mixture was stirred at 90° C.-100° C. for 10 h. Aftercompletion of reaction, reaction mixture was transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain 65.5. (0.250 g, Yield: 53.52%). MS(ES): m/z 255.98 [M+H]⁺.

Synthesis of Compound 65.6

The compound was synthesized from compounds B.2 and 65.5 using GeneralProcedure A to obtain 65.6. (0.210 g, Yield: 53.18%), MS (ES): m/z547.22 [M+H]⁺.

Synthesis of Compound 65.7

To a solution of compound 65.6 (0.210 g, 0.38 mmol, 1.0 eq), in methanol(2 mL) was added sodium hydroxide (0.076 g, 1.9 mmol, 5.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue. To this added water and acidified with 1N hydrochloricacid to adjust pH-6 at 10° C. Product was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 65.7. (0.150 g, Yield: 73.31%). MS (ES):m/z 533.21 [M+H]⁺.

Synthesis of Compound 65.8

The compound was synthesized from compound 65.7 and methylamine usingGeneral Procedure H to obtain 65.8. (0.120 g, Yield: 78.09%), MS (ES):m/z 546.24 [M+H]⁺.

Synthesis of Compound 65.9

The compound was synthesized from compound 65.8 using General ProcedureB to obtain 65.9. (0.060 g, Yield: 74.67%), MS (ES): m/z 366.14 [M+H]⁺.

Synthesis of Compound I-65

The compound was synthesized from compound 65.9 using General ProcedureC to obtain I-65 (0.030 g, Yield: 42.15%), MS (ES): m/z 434.25 [M+H]⁺LCMS purity: 100%, HPLC purity: 96.11%, ¹H NMR (DMSO-d₆, 400 MHz): 12.15(s, 1H), 11.35 (s, 1H), 8.40 (bs, 1H), 8.32 (s, 1H), 8.16 (s, 1H),7.81-7.78 (d, J=12 Hz, 2H), 8.10 (s, 1H), 7.57 (s, 1H), 3.92 (s 3H),2.60 (s, 3H), 2.20 (bs, 1H), 0.95-0.90 (m, 4H).

Example 66:7-(cyclopropanecarboxamido)-2-(2-fluoro-4-(pyrazin-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-66)

Synthesis of Compound 66.2

To a degassed solution of compound 66.1 (1.0 g, 4.58 mmol, 1.0 eq) and2-bromopyrazine (0.952 g, 5.95 mmol, 1.3 eq) in ethanol and toluene(1:1, 20 mL), potassium carbonate (1.2 g, 9.16 mmol, 2.0 eq) andtetrakis(triphenylphosphine)palladium(0) (0.528 g, 0.45 mmol, 0.1 eq)were added to it and further purging done for 10 min. Reaction wasallowed to stir at 80° C. for 5 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain 66.2. (0.350 g, Yield: 30.26%). MS (ES): m/z 253.97[M+H]⁺.

Synthesis of Compound 66.3

The compound was synthesized from compounds B.2 and 66.2 using GeneralProcedure A to obtain 66.3. (0.220 g, Yield: 56.02%), MS (ES): m/z544.21 [M+H]⁺.

Synthesis of Compound 66.4

To a solution of compound 66.3 (0.220 g, 0.40 mmol, 1.0 eq), in methanol(2 mL) was added sodium hydroxide (0.080 g, 2.0 mmol, 5.0 eq). Thereaction mixture was stirred at 60° C. for 1 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure toobtain residue. To this added water and acidified with 1N hydrochloricacid to adjust pH-6 at 10° C. Product was extracted withdichloromethane. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and compound was eluted in 2.1% methanol indichloromethane to obtain pure 66.4. (0.180 g, Yield: 83.99%). MS (ES):m/z 530.19 [M+H]⁺.

Synthesis of Compound 66.5

The compound was synthesized from compound 66.4 and methylamine usingGeneral Procedure H to obtain 66.5. (0.150 g, Yield: 81.33%), MS (ES):m/z 543.23 [M+H]⁺.

Synthesis of Compound 66.6

The compound was synthesized from compound 66.5 using General ProcedureB to obtain 66.6. (0.070 g, Yield: 69.88%), MS (ES): m/z 363.13 [M+H]⁺.

Synthesis of Compound I-66

The compound was synthesized from compound 66.6 using General ProcedureC to obtain I-66 (0.028 g, Yield: 33.67%), MS (ES): m/z 431.25 [M+H]⁺LCMS purity: 96.59%, HPLC purity: 95.77%, ¹H NMR (DMSO-d₆, 400 MHz):12.16 (s, 1H), 11.32 (s, 1H), 9.41 (bs, 1H), 8.78 (s, 1H), 8.69 (s, 1H),8.40-8.39 (d, J=4 Hz, 1H), 8.23-8.14 (m, 2H), 7.57 (s, 1H), 7.07-7.06(d, J=6.8 Hz, 1H), 6.82-6.81 (d, J=6.8 Hz, 1H), 2.86-2.85 (d, J=4.4 Hz,3H), 2.26 (bs, 1H), 1.00-0.94 (m, 4H).

Example 67:7-(cyclopropanecarboxamido)-2-(4-ethylthiazol-2-yl)-N-methyl-11H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-70)

Synthesis of Compound 67.1

To a solution of compound 67 (0.5 g, 3.90 mmol, 1.0 eq) in acetonitrile(10 ml) was added tert-Butyl nitrite (0.5 mL, 4.29 mmol, 1.1 eq) at 0°C. and stirred for 10 min. Copper (II) bromide (0.608 g, 2.73 mmol, 0.7eq) was added and reaction mixture was stirred at 0° C. for 30 min.After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and compound was eluted in2.0% ethyl acetate in hexane to obtain pure 67.1. (0.3 g, Yield:40.04%). MS(ES): m/z 191.94 [M+H]⁺.

Synthesis of Compound 67.2

Compound was synthesized as per experimental protocol of core synthesisB to obtain 67.2. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 67.3

Compound was synthesized using general procedure A to obtain 67.3. (0.2g, Yield: 49.17%), MS (ES): m/z 483.18 [M+H]⁺.

Synthesis of Compound 67.4

To a solution of 67.3 (0.2 g, 0.41 mmol, 1.0 eq) in methanol (4 mL), wasadded palladium hydroxide on carbon (20%, 0.150 g). Hydrogen was purgedthrough reaction mixture for 4 h at room temperature. After completionof reaction, reaction mixture was filtered through Celite-bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 67.4. (0.120 g, Yield: 95.77%), MS (ES): m/z303.09 [M+H]⁺.

Synthesis of Compound 67.6

Compound was synthesized using general procedure C to obtain 67.6.(0.080 g, Yield: 48.37%), MS (ES): m/z 371.11 [M+H]⁺.

Synthesis of compound I-70

To a solution of compound 67.6 (0.080 g, 0.21 mmol, 1.0 eq) intetrahydrofuran (2 mL) were added N,N-Diisopropylethylamine (0.1 mL,0.63 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.52 mL, 1.05mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.031 mL, 0.63mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain I-70(0.034 g, Yield: 42.61%), MS (ES): 370.26 [M+H]⁺ LCMS purity: 100%, HPLCpurity: 99.14%, ¹H NMR (DMSO-d₆, 400 MHZ): 8.41 (bs, 3H), 8.33 (bs, 1H),7.47-7.44 (d, J=13.2 Hz, 2H), 2.83-2.82 (m, 3H), 2.81-2.77 (m, 2H), 2.18(bs, 1H), 1.30-1.26 (t, J=7.6 Hz, 3H), 0.97-0.92 (m, 4H).

Example 68:7-(cyclopropanecarboxamido)-2-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2-fluorophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-68)

Synthesis of Compound 68.2

Compound was synthesized using general procedure A to obtain 68.2. (0.8g, Yield: 65.05%), MS (ES): m/z 270.00 [M+H]⁺

Synthesis of Compound 68.3

Compound was synthesized as per experimental protocol of core synthesisB to obtain 68.3. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺

Synthesis of Compound 68.4

Compound was synthesized using general procedure A to obtain 68.4.(0.250 g, Yield: 61.83%), MS (ES): m/z 560.24 [M+H]⁺

Synthesis of Compound 68.5

To a solution of compound 68.4 (0.250 g, 0.44 mmol, 1.0 eq) intetrahydrofuran (5 mL) were added N,N-Diisopropylethylamine (0.24 mL,1.32 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 1.1 mL, 2.2 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.66 mL, 1.32 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 68.5.(0.180 g, Yield: 72.13%), MS (ES): m/z 559.26 [M+H]⁺

Synthesis of Compound 68.6

Compound was synthesized using general procedure B to obtain 68.6.(0.120 g, Yield: 98.42%), MS (ES): m/z 379.16 [M+H]+

Synthesis of Compound I-68

Compound was synthesized using general procedure C to obtain I-68 (0.060g, Yield: 42.38%), MS (ES): 447.52 [M+H]⁺ LCMS purity: 98.45%, HPLCpurity: 97.76%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.14 (s, 1H), 11.33 (s, 1H),8.40-8.39 (d, J=4.4 Hz, 1H), 8.33 (s, 1H), 8.09-8.05 (t, J=8 Hz, 1H),7.71-7.70 (d, J=6 Hz, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 6.85 (s, 1H),3.69 (s, 3H), 2.87-2.86 (d, J=4.4 Hz, 3H), 2.26 (s, 3H), 1.24 (bs, 1H),1.00-0.95 (m, 4H).

Example 69:7-(cyclopropanecarboxamido)-2-(3-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2-fluorophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-69)

Synthesis of Compound 69.2

To the suspension of sodium hydride (1.69 g, 70.58 mmol, 1.2 eq) intetrahydrofuran (25 mL) at 0° C. was added solution of 69 (5.0 g, 58.82mmol, 1.0 eq) in tetrahydrofuran (25 mL) dropwise. Reaction mixture wasstirred at room temperature for 30 min. Then 69.1 (10.7 g, 70.58 mmol,1.2 eq) was added in to reaction mixture and stirred at room temperaturefor 2 h. After completion of reaction, reaction mixture was transferredinto ice cold water and product was extracted with ethyl acetate.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain 69.2.(5.0 g, Yield: 54.15%). MS(ES): m/z 157.07 [M+H]⁺.

Synthesis of Compound 69.3

Mixture of compound 69.2 (4.5 g, 28.66 mmol, 1.0 eq) and methanolicammonia (50 ml) was stirred at 60° C. for 4 h. After completion ofreaction, reaction mixture was concentrated under reduced pressure andtriturated with diethyl ether to obtain 69.3. (1.87 g, Yield: 45.94%).MS(ES): m/z 143.08 [M+H]⁺.

Synthesis of Compound 69.4

The mixture of compound 69.3 (1.87 g, 13.16 mmol, 1.0 eq) and Phosphorylbromide (0.9 g) was heated at 70° C. for 3 h. After completion ofreaction, reaction mixture was quenched with saturated sodiumbicarbonate solution and extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by trituration using n-pentane to obtain pure 69.4.(0.970 g, Yield: 39.42%). MS(ES): m/z 185.9 [M+H]⁺.

Synthesis of Compound 69.6

Compound was synthesized using general procedure A to obtain 69.6. (1.1g, Yield: 75.45%). MS (ES): m/z 280.0 [M+H]⁺.

Synthesis of Compound 69.7

Compound was synthesized as per experimental protocol of core synthesisB to obtain 69.7. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺

Synthesis of Compound 69.8

Compound was synthesized using general procedure A to obtain 69.8.(0.180 g, Yield: 56.85%), MS (ES): m/z 572.24 [M+H]⁺.

Synthesis of Compound 69.9

To a solution of compound 69.8 (0.180 g, 0.31 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.17 mL,0.93 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.7 mL, 1.55 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.46 mL, 0.93 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred into ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 69.9.(0.110 g, Yield: 61.22%), MS (ES): m/z 571.26 [M+H]⁺.

Synthesis of Compound 69.10

Compound was synthesized using general procedure B to obtain 69.10.(0.070 g, Yield: 93.02%), MS (ES): m/z 391.16 [M+H]⁺.

Synthesis of Compound I-69

Compound was synthesized using general procedure C to obtain I-69 (0.040g, Yield: 48.66%), MS (ES): 459.60 [M+H]⁺ LCMS purity: 100%, HPLCpurity: 97.45%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.99 (s, 1H), 11.28 (s, 1H),8.39-8.38 (d, J=4 Hz, 1H), 8.31 (s, 1H), 8.09-8.06 (t, J=7.2 Hz, 1H),7.74-7.71 (t, J=6.4 Hz, 1H), 7.60-7.59 (d, J=4.4 Hz, 1H), 7.46 (s, 1H),7.40-7.36 (d, J=7.6 Hz, 1H), 4.07-4.03 (m, 3H), 2.85-2.84 (d, J=4 Hz,3H), 1.55 (s, 4H), 1.00-0.93 (m, 4H).

Example 70:7-(cyclopropanecarboxamido)-2-(3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-2-fluorophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-73)

Synthesis of Compound 70

Compound was synthesized as per experimental protocol of I-36 to obtain70. (Yield: 85.38%), MS (ES): m/z 218.95 [M+H]⁺.

Synthesis of Compound 70.1

To the solution of compound 70 (0.2 g, 0.91 mmol, 1.0 eq) intetrahydrofuran (4 mL) was added Lawesson's reagent (0.183 g, 0.45 mmol,0.5 eq). Reaction mixture was refluxed at 60° C. for 16 h. Aftercompletion of reaction, reaction mixture was transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by column chromatography and the compound was eluted in 15%ethyl acetate in hexane to obtain 70.1. (0.160 g, Yield: 74.51%).MS(ES): m/z 234.9 [M+H]⁺.

Synthesis of Compound 70.2

To the solution of compound 70.1 (0.160 g, 0.68 mmol, 1.0 eq) in acetone(4 mL) was added methyl iodide (0.106 g, 0.74 mmol, 1.1 eq). Reactionmixture was stirred at room temperature for 15 h. After completion ofreaction, reaction mixture was filtered and solid was washed withdichloromethane. The obtained solid material was stirred with 50%aqueous potassium carbonate solution (15 mL) and extracted withdichloromethane. Organic layer was combined, dried over sodium sulfateand concentrated under reduced pressure to obtain 70.2. (0.120 g, Yield:70.76%). MS(ES): m/z 248.9 M+H]⁺.

Synthesis of Compound 70.4

To the solution of compound 70.2 (0.120 g, 0.48 mmol, 1.0 eq) in ethanol(2 mL) was added 70.3. (0.035 g, 0.48 mmol, 1.0 eq). Reaction mixturewas refluxed at 100° C. for 1 h. After completion of reaction, reactionmixture was filtered through millipore and concentrated under reducedpressure to obtain 70.4. (0.082 g, Yield: 66.21%). MS(ES): m/z 255.9[M+H]⁺.

Synthesis of Compound 70.5

To a solution of 70.4 (0.082 g, 0.32 mmol, 1.0 eq) inN,N-dimethylformamide (2 mL), was added sodium hydride (0.015 g, 0.64mmol, 2.0 eq) at 0° C. and stirred for 20 min. Methyl iodide (0.049 g,0.35 mmol, 1.1 eq) was added and reaction mixture was stirred at 50° C.for 2 h. After completion of reaction, reaction mixture was transferredinto ice, stirred and extracted with ethyl acetate. Organic layer wascombined, dried over sodium sulfate and concentrated under reducedpressure to obtain 70.5. (0.022 g, Yield: 25.44%). MS (ES): m/z270.9[M+H]⁺.

Synthesis of Compound 70.6

Compound was synthesized as per experimental protocol of core synthesisB to obtain 70.6. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 70.7

Compound was synthesized using general procedure A to obtain 70.7.(0.190 g, Yield: 43.30%), MS (ES): m/z 561.24 [M+H]⁺.

Synthesis of Compound 70.8

To a solution of compound 70.7 (0.190 g, 0.33 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.18 mL,0.99 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.82 mL, 1.65mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.49 mL, 0.99mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 16 h.After completion of reaction, reaction mixture was transferred to icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 70.8.(0.150 g, Yield: 79.09%), MS (ES): m/z 560.25 [M+H]⁺.

Synthesis of Compound 70.9

Compound was synthesized using general procedure B to obtain 70.9.(0.090 g, Yield: 88.51%), MS (ES): m/z 380.16 [M+H]⁺.

Synthesis of Compound I-73

Compound was synthesized using general procedure C to obtain I-73 (0.050g, Yield: 47.10%), MS (ES): 448.72 [M+H]⁺ LCMS purity: 98.58%, HPLCpurity: 98.17%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.25 (s, 1H), 11.41 (s, 1H),8.39 (s, 1H), 8.32 (bs, 1H), 8.03-8.01 (d, J=6.8 Hz, 2H), 7.50-7.44 (m,2H), 3.89 (s, 3H), 2.86-2.85 (d, J=4.8 Hz, 3H), 2.84 (s, 3H), 1.65 (s,1H), 0.99-0.94 (m, 4H).

Example 71:7-(cyclopropanecarboxamido)-2-(2-fluoro-4-(1,4,5-trimethyl-1H-imidazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-74)

Synthesis of Compound 71.1

To the solution of compound 71 (4.2 g, 38.18 mmol, 1.0 eq) intetrahydrofuran (42 mL) was added dropwise Lithium diisopropylamide (2Min tetrahydrofuran), (57 mL, 114.54 mmol, 3.0 eq) at −78° C. Thereaction mixture was stirred at −78° C. for 1 h. Then a solution ofiodine (9.6 g, 76.36 mmol, 2.0 eq) in tetrahydrofuran (20 mL) was addedto reaction mixture and stirred for 2 h at same temperature. Aftercompletion of reaction, reaction mixture was transferred into ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 7% ethyl acetate in hexane to obtain 71.1. (1.6 g,Yield: 17.78%). MS (ES): m/z 236.9 [M+H]⁺.

Synthesis of Compound 71.3

Argon was purged for 15 min through a stirred mixture of 71.1 (1.6 g,6.77 mmol, 1.0 eq), 71.2 (1.9 g, 8.80 mmol, 1.3 eq) and sodium carbonate(1.7 g, 16.92 mmol, 2.5 eq) in toluene (30 mL).Tetrakis(triphenylphosphine)palladium(0) (0.781 g, 0.67 mmol, 0.1 eq)was added to it and further purging done for 10 min. Reaction wasallowed to stirr at 80° C. for 5 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain 71.3. (0.7 g, Yield: 36.47%). MS (ES): m/z284.01[M+H]⁺.

Synthesis of Compound 71.4

Compound was synthesized as per experimental protocol of core synthesisB to obtain 71.4. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 71.5

Compound was synthesized using general procedure A to obtain 71.5.(0.160 g, Yield: 45.42%), MS (ES): m/z 574.26 [M+H]⁺.

Synthesis of Compound 71.6

To a solution of compound 71.5 (0.160 g, 0.27 mmol, 1.0 eq) intetrahydrofuran (2 mL) were added N,N-Diisopropylethylamine (0.14 mL,0.81 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.6 mL, 1.35 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.4 mL, 0.81 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 71.6.(0.127 g, Yield: 79.51%), MS (ES): m/z 573.27 [M+H]⁺.

Synthesis of Compound 71.7

Compound was synthesized using general procedure B to obtain 71.7.(0.067 g, Yield: 76.99%), MS (ES): m/z 393.18 [M+H]⁺.

Synthesis of Compound I-74

Compound was synthesized using general procedure C to obtain I-74 (0.032g, Yield: 40.70%), MS (ES): 461.67 [M+H]⁺ LCMS purity: 97.11%, HPLCpurity: 96.81%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.13 (s, 1H), 11.33 (s, 1H),8.40-8.39 (d, J=4.4 Hz, 1H), 8.33 (s, 1H), 8.06-8.02 (t, J=8 Hz, 1H),7.67 (bs, 1H), 7.65 (bs, 1H), 7.52 (bs, 1H), 3.66 (s, 3H), 2.87-2.86 (d,J=4.4 Hz, 3H), 2.27 (bs, 1H), 2.19 (s, 3H), 2.12 (s, 3H), 1.00-0.95 (m,4H).

Example 72:7-(cyclopropanecarboxamido)-2-(2-fluoro-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-3-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-75)

Synthesis of Compound 72.1

To the solution of compound 72 (5.0 g, 42.37 mmol, 1.0 eq) inTrifluoroacetic acid (50 mL) was added platinum dioxide (0.5 g).Hydrogen was purged through reaction mixture for 30 min at roomtemperature. Then reaction mixture was stirred under Hydrogen pressurefor 18 h. After completion of reaction, reaction mixture wasconcentrated and neutralized by using aqueous sodium hydroxide thenextracted with 5% methanol in dichloromethane. Organic layer wascombined, dried over sodium sulfate and concentrated under reducedpressure to obtain 72.1. (2.73 g, Yield: 52.80%). MS (ES): m/z 123.09[M+H]⁺.

Synthesis of Compound 72.2

To a solution of compound 72.1 (2.73 g, 22.37 mmol, 1.0 eq) inAcetonitrile (30 mL) was added Cyanogen bromide (2.3 g, 22.37 mmol, 1.0eq). Reaction mixture was stirred at room temperature for 18 h. Aftercompletion of reaction, reaction mixture was transferred into aqueoussodium bicarbonate solution and extracted with ethyl acetate. Organiclayer was combined, washed with brine solution, dried over sodiumsulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by 20% ethyl acetate in hexane toobtain 72.2. (2.0 g, Yield: 44.51%), MS (ES): m/z 201.9 [M+H]⁺.

Synthesis of Compound 72.4

Compound was synthesized using general procedure A to obtain 72.4.(0.210 g, Yield: 7.15%), MS (ES): m/z 295.16 [M+H]⁺.

Synthesis of Compound 72.5

Compound was synthesized as per experimental protocol of core synthesisB to obtain 72.5. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 72.6

Compound was synthesized using general procedure A to obtain 72.6.(0.170 g, Yield: 48.21%), MS (ES): m/z 586.26 [M+H]⁺.

Synthesis of Compound 72.7

To a solution of compound 72.6 (0.170 g, 0.29 mmol, 1.0 eq) intetrahydrofuran (2 mL) were added N,N-diisopropylethylamine (0.16 mL,0.87 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.72 mL, 1.45mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.43 mL, 0.87mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 72.7.(0.150 g, Yield: 88.38%), MS (ES): m/z 585.27 [M+H]⁺.

Synthesis of Compound 72.8

Compound was synthesized using general procedure B to obtain 72.8.(0.080 g, Yield: 77.10%), MS (ES): m/z 405.18 [M+H]⁺.

Synthesis of Compound I-75

Compound was synthesized using general procedure C to obtain I-75 (0.042g, Yield: 44.94%), MS (ES): 473.67 [M+H]⁺ LCMS purity: 100%, HPLCpurity: 97.95%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.12 (s, 1H), 11.33 (s, 1H),8.40-8.39 (d, J=4 Hz, 1H), 8.33 (s, 1H), 8.07-8.03 (t, J=8.4 Hz, 1H),7.75 (bs, 1H), 7.72-7.71 (d, J=3.2 Hz, 1H), 7.52 (s, 1H), 6.85 (s, 1H),4.23-4.20 (t, J=5.6 Hz, 2H), 2.87-2.86 (d, J=4.4 Hz, 3H), 2.27 (bs, 1H),1.90 (bs, 3H), 1.79 (bs, 3H), 1.00-0.95 (m, 4H).

Example 73:7-(cyclopropanecarboxamido)-2-(3-(6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-2-yl)-2-fluorophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-76)

Synthesis of Compound 73.1

Mixture of compound 73 (4.0 g, 30.76 mmol, 1.0 eq) and sodium cyanate(1.9 g, 30.76 mmol, 1.0 eq) in water (10 mL) was stirred at 90° C. for 2h. After completion of reaction, reaction mixture was concentrated underreduced pressure to obtained semi solid material which was treated withhot ethanol. Ethanol layer was cooled and diethyl ether was added.Precipitated solid was filtered and dried to obtain 73.1. (2.2 g, Yield:71.42%). MS(ES): m/z 136.04 [M+H]⁺.

Synthesis of Compound 73.3

To the solution of compound 73.1 (0.3 g, 2.22 mmol, 1.0 eq) and 73.2(0.654 g, 2.22 mmol, 1.0 eq) in Dimethylformamide (10 mL) was addedSodium carbonate (1.1 g, 11.1 mmol, 5.0 eq). Reaction mixture was heatedat 80° C. for 16 h. After completion of reaction, reaction mixture wastransferred into water and product was extracted with ethyl acetate.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography and thecompound was eluted in 20% ethyl acetate in hexane to obtain 73.3.(0.150 g, Yield: 16.85%). MS(ES): m/z 297.9 [M+H]⁺.

Synthesis of Compound 73.4

Compound was synthesized as per experimental protocol of core synthesisB to obtain 73.4. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺

Synthesis of Compound 73.5

Compound was synthesized using general procedure A to obtain 73.5.(0.170 g, Yield: 48.05%), MS (ES): m/z 588.24 [M+H]⁺.

Synthesis of Compound 73.6

To a solution of compound 73.5 (0.170 g, 0.28 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.15 mL,0.84 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.7 mL, 1.4 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.42 mL, 0.84 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 73.6.(0.123 g, Yield: 72.47%), MS (ES): m/z 587.25 [M+H]⁺.

Synthesis of Compound 73.7

Compound was synthesized using general procedure B to obtain 73.7.(0.075 g, Yield: 88.02%), MS (ES): m/z 407.16 [M+H]⁺.

Synthesis of Compound I-76

Compound was synthesized using general procedure C to obtain I-76 (0.030g, Yield: 34.26%), MS (ES): 475.62 [M+H]⁺ LCMS purity: 99.35%, HPLCpurity: 97.36%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.97 (s, 1H), 11.29 (s, 1H),8.40-8.39 (d, J=4.4 Hz, 1H), 8.33 (s, 1H), 7.98-7.95 (t, J=6.8 Hz, 1H),7.73-7.69 (t, J=7.6 Hz, 1H), 7.47 (s, 1H), 7.39-7.35 (d, J=7.6 Hz, 1H),7.31-7.29 (d, J=4.4 Hz, 1H), 4.40 (bs, 1H), 4.08-3.97 (m, 4H), 2.86-2.85(d, J=4.4 Hz, 3H), 1.56 (bs, 2H), 1.02-0.95 (m, 4H).

Example 74:7-(cyclopropanecarboxamido)-2-(2,6-difluoro-4-(1-methyl-1H-imidazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-77)

Synthesis of Compound 74.1

To a solution of 74 (3.0 g, 14.42 mmol, 1.0 eq) in dimethyl sulfoxide(60 mL) was added Bis(pinacolato)diboron (4.0 g, 15.86 mmol, 1.1 eq),and potassium acetate (4.2 g, 43.26 mmol, 3.0 eq). The reaction mixturewas degassed for 10 min. under argon atmosphere, then[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.171 g,0.21 mmol, 0.015 eq) was added, and degassed for 5 min. The reactionmixture was stirred at 80° C. for 1 h. After completion of reaction,reaction mixture was cooled to room temperature, transferred into waterand product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by combi flash using 3% methanol in dichloromethane aseluant to obtain pure 74.1. (1.8 g, Yield: 48.93%). MS(ES): m/z 254.13[M+H]⁺.

Synthesis of Compound 74.3

Compound was synthesized using general procedure A to obtain 74.3. (0.6g, Yield: 40.64%). MS (ES): m/z 210.08 [M+H]⁺.

Synthesis of Compound 74.4

To a solution of compound 74.3 (0.550 g, 2.63 mmol, 1.0 eq) inacetonitrile (10 mL) was added tert-Butyl nitrite (0.541 g, 5.26 mmol,2.0 eq) and reaction mixture was cooled to 0° C. Then Copper (II)bromide (l.1 g, 5.26 mmol, 2.0 eq) was added to reaction mixture andstirred at room temperature for 2 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by combiflash using 20% ethyl acetate in hexane as eluant to obtain pure 74.4.(0.260 g, Yield: 36.21%). MS(ES): m/z 271.9 [M+H]⁺.

Synthesis of Compound 74.5

Compound was synthesized as per experimental protocol of core synthesisB to obtain 74.5. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 74.6

Compound was synthesized using general procedure A to obtain 74.6.(0.180 g, Yield: 53.05%), MS (ES): m/z 564.22 [M+H]⁺.

Synthesis of Compound 74.7

To a solution of compound 74.6 (0.180 g, 0.31 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.17 mL,0.93 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.7 mL, 1.55 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.46 mL, 0.93 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 74.7.(0.110 g, Yield: 61.22%), MS (ES): m/z 563.23 [M+H]⁺.

Synthesis of Compound 74.8

Compound was synthesized using general procedure B to obtain 74.8.(0.070 g, Yield: 93.63%), MS (ES): m/z 383.14 [M+H]⁺.

Synthesis of Compound I-77

Compound was synthesized using general procedure C to obtain I-77 (0.040g, Yield: 48.51%), MS (ES): 451.37 [M+H]⁺ LCMS purity: 100%, HPLCpurity: 97.24%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.29 (s, 1H), 11.42 (s, 1H),8.46 (s, 1H), 8.34 (s, 1H), 7.71-7.68 (t, J=10.8 Hz, 2H), 7.55 (bs, 1H),7.38 (bs, 1H), 6.82 (bs, 1H), 3.89 (bs, 3H), 2.84 (bs, 3H), 1.54 (bs,1H), 0.96-0.85 (m, 4H).

Example 75:7-(cyclopropanecarboxamido)-2-(2-ethoxy-6-fluoro-4-(1-methyl-1H-imidazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-78)

Synthesis of Compound 75.1

To a solution of 75 (5.0 g, 21 mmol, 1.0 eq) in ethanol (50 mL) wasadded Potassium hydroxide (2.3 g, 42 mmol, 2.0 eq). The reaction mixturewas stirred at 90° C. for 5 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 10% ethyl acetate in hexane as eluant toobtain pure 75.1. (3.2 g, Yield: 57.68%). MS (ES): m/z 264.9 [M+H]⁺.

Synthesis of Compound 75.2

To a solution of 75.1 (1.0 g, 3.78 mmol, 1.0 eq) in Acetic acid (2.1 mL,37.8 mmol, 10.0 eq) was added Iron powder (1.0 g, 18.9 mmol, 5.0 eq).Reaction mixture was stirred at 90° C. for 30 min. After completion ofreaction, reaction mixture was cooled to room temperature and filteredthrough Celite-bed. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and the compound was eluted in 5% ethyl acetate in hexaneto obtain 75.2. (0.7 g, Yield: 78.97%), MS (ES): m/z 234.9 [M+H]⁺.

Synthesis of Compound 75.3

To a solution of 75.2 (0.7 g, 2.99 mmol, 1.0 eq) in 1,4-dioxane (15 mL)was added Bis(pinacolato)diboron (0.835 g, 3.28 mmol, 1.1 eq), andPotassium acetate (0.880 g, 8.97 mmol, 3.0 eq). The reaction mixture wasdegassed for 15 min under argon atmosphere, thenTris(dibenzylideneacetone)dipalladium(0) (0.190 g, 0.20 mmol, 0.07 eq)and 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.142 g, 0.29mmol, 0.1 eq) were added and again degassed for 5 min. The reactionmixture was stirred at 110° C. for 4 h. After completion of reaction,reaction mixture was cooled to room temperature, transferred into waterand product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by combi flash using 4% ethyl acetate in hexane aseluant to obtain pure 75.3. (0.560 g, Yield: 66.61%). MS(ES): m/z 281.1[M+H]⁺.

Synthesis of Compound 75.5

Argon was purged for 15 min through a stirred solution of 75.3 (0.560 g,1.99 mmol, 1.0 eq), and 75.4 (0.416 g, 2.58 mmol, 1.3 eq) indimethylformamide (8 mL). Bis(triphenylphosphine)palladium(II)dichloride (0.139 g, 0.19 mmol, 0.1 eq) was added to it and the mixturewas further purged for 10 min. Reaction was stirred at 60° C. for 5 h.After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain 75.5. (0.362 g, Yield:77.25%). MS (ES): m/z 236.1 [M+H]⁺.

Synthesis of Compound 75.6

To a solution of compound 75.5 (0.3 g, 1.27 mmol, 1.0 eq) inacetonitrile (6 ml) was added tert-Butyl nitrite (0.261 g, 2.54 mmol,2.0 eq) and the reaction mixture was cooled to 0° C. Copper (II) bromide(0.566 g, 2.54 mmol, 2.0 eq) was added to reaction mixture and stirredat room temperature for 2 h. After completion of reaction, reactionmixture was transferred into water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by combi flash using 20% ethylacetate in hexane as eluant to obtain pure 75.6. (0.150 g, Yield:39.32%). MS(ES): m/z 299.1 [M+H]⁺.

Synthesis of Compound 75.7

Compound was synthesized as per experimental protocol of core synthesisB to obtain 75.7. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 75.8

Compound was synthesized using general procedure A to obtain 75.8.(0.120 g, Yield: 33.80%), MS (ES): m/z 590.25 [M+H]⁺.

Synthesis of Compound 75.9

To a solution of compound 75.8 (0.120 g, 0.20 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.11 mL,0.6 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.5 mL, 1.0 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.3 mL, 0.6 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 75.9.(0.060 g, Yield: 50.08%), MS (ES): m/z 589.2 [M+H]⁺.

Synthesis of Compound 75.10

Compound was synthesized using general procedure B to obtain 75.10.(0.033 g, Yield: 79.27%), MS (ES): m/z 409.1 [M+H]⁺.

Synthesis of compound I-78

Compound was synthesized using general procedure C to obtain I-78 (0.025g, Yield: 64.93%), MS (ES): 477.67 [M+H]⁺ LCMS purity: 100%, HPLCpurity: 99.72%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.20 (s, 1H), 11.34 (s, 1H),8.40-8.39 (d, J=4.4 Hz, 1H), 7.53 (s, 1H), 7.38-7.34 (d, J=12.6 Hz, 1H),7.07-7.04 (d, J=11.6 Hz, 2H), 6.82 (bs, 2H), 4.36-4.32 (m, 1H), 3.84(bs, 3H), 2.83-2.82 (d, J=4 Hz, 3H), 2.23 (bs, 1H), 1.48-1.44 (t, J=6.8Hz, 3H), 1.22 (bs, 1H), 0.95-0.85 (m, 4H).

Example 76:7-(cyclopropanecarboxamido)-2-(3-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)-2-fluorophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-79)

Synthesis of Compound 76.1

To the solution of compound 76 (1.8 g, 17.82 mmol, 1.0 eq) intetrahydrofuran (30 mL) was added Lawesson's reagent (3.59 g, 8.91 mmol,0.5 eq). Reaction mixture was refluxed for 16 h. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 15% ethyl acetate inhexane to obtain 76.1. (1.0 g, Yield: 47.94%). MS(ES): m/z 119.02[M+H]⁺.

Synthesis of Compound 76.2

To the solution of compound 76.1 (1.5 g, 12.71 mmol, 1.0 eq) indichloromethane (25 mL) was added methyl iodide (1.9 g, 13.98 mmol, 1.1eq). Reaction mixture was stirred at room temperature for 15 h. Aftercompletion of reaction, reaction mixture was filtered and solid waswashed with dichloromethane. The obtained solid material was dissolvedwith 50% aqueous potassium carbonate solution (15 mL) and extracted withdichloromethane. Organic layer was combined, dried over sodium sulfateand concentrated under reduced pressure to obtain 76.2. (0.8 g, Yield:47.63%). MS(ES): m/z 131.04 [M+H]⁺.

Synthesis of Compound 76.3

To the solution of compound 76.2 (0.8 g, 6.15 mmol, 1.0 eq) in ethanol(15 mL) was added ammonium chloride (0.332 g, 6.15 mmol, 1.0 eq).Reaction mixture was refluxed for 1 h. After completion of reaction,reaction mixture was filtered through millipore and concentrated underreduced pressure to obtain 76.3. (0.7 g, Yield: 84.05%). MS(ES): m/z136.04 [M+H]⁺.

Synthesis of Compound 76.5

To the solution of compound 76.3 (0.3 g, 2.22 mmol, 1.0 eq) and 76.4(0.654 g, 2.22 mmol, 1.0 eq) in Dimethylformamide (10 mL) was addedSodium carbonate (1.1 g, 11.1 mmol, 5.0 eq). Reaction mixture was heatedat 80° C. for 16 h. After completion of reaction, reaction mixture wastransferred into water and product was extracted with ethyl acetate.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography and thecompound was eluted in 20% ethyl acetate in hexane to obtain 76.5.(0.190 g, Yield: 29.11%). MS(ES): m/z 297.9 [M+H]⁺.

Synthesis of Compound 76.6

Compound was synthesized as per experimental protocol of core synthesisB to obtain 76.6. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 76.7

Compound was synthesized using general procedure A to obtain 76.7.(0.170 g, Yield: 48.05%), MS (ES): m/z 588.24 [M+H]⁺.

Synthesis of Compound 76.8

To a solution of compound 76.7 (0.170 g, 0.28 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.15 mL,0.84 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.7 mL, 1.4 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.42 mL, 0.84 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 76.8.(0.120 g, Yield: 70.71%), MS (ES): m/z 587.25 [M+H]⁺.

Synthesis of Compound 76.9

Compound was synthesized using general procedure B to obtain 76.9.(0.070 g, Yield: 84.20%), MS (ES): m/z 407.16 [M+H]⁺.

Synthesis of Compound I-79

Compound was synthesized using general procedure C to obtain I-79 (0.028g, Yield: 34.26%), MS (ES): 475.66 [M+H]⁺ LCMS purity: 98.48%, HPLCpurity: 98.20%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.97 (s, 1H), 11.29 (s, 1H),8.40-8.39 (d, J=4.4 Hz, 1H), 8.31 (s, 1H), 8.09-8.05 (t, J=7.2 Hz, 1H),7.76-7.73 (t, J=7.2 Hz, 1H), 7.66-7.65 (d, J=4.4 Hz, 1H), 7.47 (s, 1H),7.41-7.37 (d, J=8 Hz, 1H), 4.82 (s, 1H), 4.13-4.05 (m, 4H), 2.85-2.84(d, J=4.4 Hz, 3H), 1.54 (bs, 2H), 1.00-0.94 (m, 4H).

Example 77:7-(cyclopropanecarboxamido)-N-methyl-2-(1′-methyl-1′H-[1,4′-bipyrazol]-3-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-80)

Synthesis of Compound 77.2

To a solution of 77 (3.0 g, 15.46 mmol, 1.0 eq) and 77.1 (3.8 g, 18.55mmol, 1.2 eq) in 1,4-dioxane (60 mL) was added potassium carbonate (4.2g, 30.92 mmol, 2.0 eq) and the reaction mixture was degassed with argonfor 15 min. Copper iodide (0.588 g, 3.09 mmol, 0.2 eq) andtrans-N,N′-Dimethylcyclohexane-1,2-diamine (0.878 g, 6.18 mmol, 0.4 eq)were added and reaction mixture again was degassed with argon for 5 minfollowed by heating at 100° C. for 48 h. After completion of reaction,reaction mixture was cooled to room temperature, transferred into waterand product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and compound was eluted in1.2% methanol in dichloromethane to obtain pure 77.2. (0.859 g, Yield:20.27%). MS(ES): m/z 274.9 [M+H]⁺.

Synthesis of Compound 77.3

Compound was synthesized as per experimental protocol of core synthesisB to obtain 77.3. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 77.4

Compound was synthesized using general procedure A to obtain 77.4.(0.190 g, Yield: 50.81%), MS (ES): m/z 518.23 [M+H]⁺.

Synthesis of Compound 77.5

To a solution of compound 77.4 (0.190 g, 0.36 mmol, 1.0 eq) intetrahydrofuran (2 mL) were added N,N-Diisopropylethylamine (0.19 mL,1.08 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.9 mL, 1.8 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.54 mL, 1.08 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 77.5.(0.148 g, Yield: 78.07%), MS (ES): m/z 517.24 [M+H]⁺.

Synthesis of Compound 77.6

Compound was synthesized using general procedure B to obtain 77.6.(0.052 g, Yield: 53.96%), MS (ES): m/z 337.15 [M+H]⁺.

Synthesis of Compound I-80

Compound was synthesized using general procedure C to obtain I-80 (0.022g, Yield: 35.19%), MS (ES): 405.67 [M+H]⁺ LCMS purity: 97.82%, HPLCpurity: 96.75%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.01 (s, 1H), 11.51 (s, 1H),8.41-8.40 (d, J=4 Hz, 1H), 8.31 (bs, 1H), 8.27 (bs, 2H), 7.92 (s, 1H),7.39 (s, 1H), 7.13 (bs, 1H), 3.92 (bs, 3H), 2.85-2.86 (d, J=4.4 Hz, 3H),2.28 (s, 1H), 1.02-0.92 (m, 4H).

Example 78:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-(2-methyloxazol-5-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-81)

Synthesis of Compound 78.1

To the solution of Iodosobenzene (0.765 g, 3.48 mmol, 1.5 eq) andtriflic acid (0.5 g, 2.31 mmol, 3.0 eq) in Acetonitrile (10 mL) wasadded 78 (1.0 g, 6.96 mmol, 1.0 eq) at 0° C. Reaction mixture wasstirred at 80° C. for 1.5 h. After completion of reaction, reactionmixture was transferred into water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by 15% ethyl acetate in hexaneto obtain 78.1. (0.2 g, Yield: 33.90%), MS (ES): m/z 254.9 [M+H]⁺.

Synthesis of Compound 78.2

Compound was synthesized as per experimental protocol of core synthesisB to obtain 78.2. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 78.3

Compound was synthesized using general procedure A to obtain 78.3.(0.180 g, Yield: 45.58%), MS (ES): m/z 546.21 [M+H]⁺.

Synthesis of Compound 78.4

To a solution of compound 78.3 (0.180 g, 0.32 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.17 mL,0.96 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.8 mL, 1.6 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.48 mL, 0.96 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred into ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 78.4.(0.110 g, Yield: 61.22%), MS (ES): m/z 546.23 [M+H]⁺.

Synthesis of Compound 78.5

Compound was synthesized using general procedure B to obtain 78.5.(0.055 g, Yield: 74.67%), MS (ES): m/z 366.13 [M+H]⁺.

Synthesis of compound I-81

Compound was synthesized using general procedure C to obtain I-81 (0.025g, Yield: 38.32%), MS (ES): 434.67 [M+H]⁺ LCMS purity: 96.41%, HPLCpurity: 95.31%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.01 (s, 1H), 11.29 (s, 1H),8.42-8.41 (d, J=4.4 Hz, 1H), 8.34 (s, 1H), 7.94-7.91 (t, J=7.2 Hz, 1H),7.84-7.80 (t, J=7.2 Hz, 1H), 7.56-7.55 (d, J=3.6 Hz, 1H), 7.50 (s, 1H),7.08 (bs, 1H), 2.89-2.88 (d, J=4.4 Hz, 3H), 2.54 (s, 3H), 1.58 (bs, 1H),0.95-0.86 (m, 4H).

Example 79:7-(cyclopropanecarboxamido)-2-(2-cyclopropoxy-6-fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-82)

Synthesis of Compound 79.1

To a solution of 79 (5.0 g, 37.87 mmol, 1.5 eq) in sulfuric acid (17 mL)was added nitric acid (23 mL) dropwise at 0° C. Reaction mixture wasstirred at 0° C. for 2 h. After completion of reaction, reaction mixturewas transferred to ice and product was extracted with ethyl acetate.Organic layer was combined, dried over sodium sulfate and concentratedunder reduced pressure to obtain 79.1. (3.2 g, Yield: 47.74%), MS (ES):m/z 178.01 [M+H]⁺.

Synthesis of Compound 79.3

To a solution of 79.1 (3.2 g, 18.07 mmol, 1.0 eq) and 79.2 (1.3 g, 19.87mmol, 1.1 eq) in dimethyl sulphoxide (35 mL) was added potassiumcarbonate (4.9 g, 36.14 mmol, 2.0 eq) and reaction mixture was stirredat 90° C. for 1 h. After completion of reaction, reaction mixture wascooled to room temperature, transferred into ice cold water and productwas extracted with ethyl acetate. Organic layer was combined, dried oversodium sulfate and concentrated under reduced pressure to obtain 79.3(2.05 g, Yield: 50.15%). MS(ES): m/z 227.03 [M+H]⁺.

Synthesis of Compound 79.4

To a solution of cyclopropanol (0.526 g, 9.07 mmol, 1.0 eq) intetrahydrofuran (40 mL) was added Sodium hydride (60%) (1.0 g, 45.35mmol, 5.0 eq) slowly at 0° C. under nitrogen atmosphere. After 10 min,79.3 (2.05 g, 9.07 mmol, 1.0 eq) was added to the reaction mixture whichwas stirred at room temperature for 2 h. After completion of reaction,reaction mixture was transferred into ice cold water and product wasextracted with ethyl acetate. Organic layer was combined, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by column chromatography and thecompound was eluted in 10% ethyl acetate in hexane to obtain 79.4. (1.72g, Yield: 71.81%). MS(ES): m/z 265.07 [M+H]⁺.

Synthesis of Compound 79.5

To a solution of 79.4 (1.72 g, 6.51 mmol, 1.0 eq) in methanol (25 mL),was added 10% palladium on charcoal (0.8 g). Hydrogen was purged throughreaction mixture for 4 h at room temperature. After completion ofreaction, reaction mixture was filtered through Celite-bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 79.5. (0.4 g, Yield: 26.23%). MS (ES): m/z235.10 [M+H]⁺.

Synthesis of Compound 79.6

To a solution of 79.5 (0.5 g, 2.13 mmol, 1.0 eq) in Acetonitrile (5 mL)was added Copper (II) bromide (0.9 g, 4.04 mmol, 1.9 eq) at 0° C. Thentert-Butyl nitrite (0.5 mL, 4.26 mmol, 2.0 eq) was added dropwise toreaction mixture at 0° C. and stirred at room temperature for 1 h. Aftercompletion of reaction, reaction mixture was transferred into water andproduct was extracted with dichloromethane. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by column chromatography and the compound was eluted in 3%ethyl acetate in hexane to obtain 79.6. (0.280 g, Yield: 44.00%), MS(ES): m/z 298.9 [M+H]⁺.

Synthesis of Compound 79.7

Compound was synthesized as per experimental protocol of core synthesisB to obtain 79.7. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 79.8

Compound was synthesized using general procedure A to obtain 79.8.(0.195 g, Yield: 34.39%), MS (ES): m/z 589.2 [M+H]⁺.

Synthesis of Compound 79.9

To a solution of compound 79.8 (0.195 g, 0.33 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.18 mL,0.99 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.82 mL, 1.65mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.49 mL, 0.99mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred to icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 79.9.(0.110 g, Yield: 56.50%), MS (ES): m/z 588.25 [M+H]⁺.

Synthesis of Compound 79.10

Compound was synthesized using general procedure B to obtain 79.10.(0.045 g, Yield: 59.01%), MS (ES): m/z 408.15 [M+H]⁺.

Synthesis of Compound I-82

Compound was synthesized using general procedure C to obtain I-82 (0.024g, Yield: 45.70%), MS (ES): 476.41 [M+H]⁺ LCMS purity: 96.69%, HPLCpurity: 97.28%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.26 (s, 1H), 10.68 (s, 1H),8.54-8.53 (d, J=4.4 Hz, 1H), 8.10 (s, 1H), 7.70-7.68 (d, J=6.8 Hz, 1H),7.24-7.22 (d, J=7.6 Hz, 1H), 7.11-7.09 (d, J=9.2 Hz, 2H), 6.81 (s, 1H),3.98 (bs, 3H), 2.81-2.80 (d, J=4.4 Hz, 3H), 1.99 (bs, 1H), 1.77-1.74 (t,J=6.8 Hz, 2H), 1.55 (bs, 1H), 1.23 (bs, 3H).

Example 80:7-(cyclopropanecarboxamido)-2-(2-(3,3-difluoropyrrolidin-1-yl)-6-fluoro-4-(1-methyl-1H-imidazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-83)

Synthesis of Compound 80.2

To a solution of 80 (10 g, 42.01 mmol, 1.5 eq) and 80.1 (7.2 g, 50.41mmol, 1.2 eq) in Acetonitrile (300 mL) was added Potassium carbonate(14.0 g, 105.02 mmol, 2.5 eq). Reaction mixture was stirred at roomtemperature for 16 h. After completion, reaction mixture was transferredinto water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and the compound was eluted in2% ethyl acetate in hexane to obtain 80.2. (6 g, Yield: 43.92%), MS(ES): m/z 325.9 [M+H]⁺.

Synthesis of Compound 80.3

To a solution of 80.2 (2.0 g, 6.15 mmol, 1.5 eq) in Acetic acid (3.5 mL,61.5 mmol, 10.0 eq) was added Iron powder (1.7 g, 30.75 mmol, 5.0 eq).Reaction mixture was stirred at 90° C. for 30 min. After completion ofreaction, reaction mixture was cooled to room temperature and filteredthrough Celite-bed. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and the compound was eluted in 5% ethyl acetate in hexaneto obtain 80.3. (1.12 g, Yield: 61.69%), MS (ES): m/z 296.0 [M+H]⁺.

Synthesis of Compound 80.4

To a solution of 80.3 (1.12 g, 3.79 mmol, 1.0 eq) in 1,4-dioxane (22 mL)was added Bis(pinacolato)diboron (1.0 g, 4.16 mmol, 1.1 eq), andPotassium acetate (1.1 g, 11.37 mmol, 3.0 eq). The reaction mixture wasdegassed for 15 min under argon atmosphere, thenTris(dibenzylideneacetone)dipalladium(0) (0.237 g, 0.26 mmol, 0.07 eq)and 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.180 g, 0.37mmol, 0.1 eq) were added and again degassed for 5 min. The reactionmixture was stirred at 110° C. for 4 h. After completion of reaction,reaction mixture was cooled to room temperature, transferred into waterand product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by combi flash using 4% ethyl acetate in hexane aseluant to obtain pure 80.4. (0.620 g, Yield: 47.74%). MS(ES): m/z 342.1[M+H]⁺.

Synthesis of Compound 80.6

To a solution of 80.4 (0.5 g, 1.46 mmol, 1.0 eq) in 1,4-dioxane (5 mL)were added 80.5 (0.164 g, 1.022 mmol, 0.7 eq) and 2M Sodium carbonatesolution (3.8 mL). The reaction mixture was degassed for 15 min underargon atmosphere, then[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.119 g, 0.14 mmol, 0.1 eq) was added and againdegassed for 5 min. The reaction mixture was stirred at 100° C. for 1 h.After completion of reaction, reaction mixture was cooled to roomtemperature, transferred into water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by combi flash using 7% ethylacetate in hexane as eluant to obtain pure 80.6 (0.310 g, Yield:71.60%). MS(ES): m/z 297.13 [M+H]⁺.

Synthesis of Compound 80.7

To a solution of 80.6 (0.260 g, 0.87 mmol, 1.0 eq) in Acetonitrile (3mL) was added Copper (II) bromide (0.368 g, 1.65 mmol, 1.9 eq) at 0° C.Then tert-Butyl nitrite (0.20 g, 1.74 mmol, 2.0 eq) was added dropwiseto reaction mixture at 0° C. and stirred for 1 h. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with dichloromethane. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 3% ethyl acetate in hexaneto obtain 80.7 (0.178 g, Yield: 56.32%), MS (ES): m/z 360.1 [M+H]⁺.

Synthesis of Compound 80.8

Compound was synthesized as per experimental protocol of core synthesisB to obtain 80.8. (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 80.9

Compound was synthesized using general procedure A to obtain 80.9.(0.192 g, Yield: 49.01%), MS (ES): m/z 651.27 [M+H]⁺.

Synthesis of Compound 80.10

To a solution of compound 80.9 (0.192 g, 0.29 mmol, 1.0 eq) intetrahydrofuran (2 mL) were added N,N-diisopropylethylamine (0.16 mL,0.87 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.72 mL, 1.45mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.43 mL, 0.87mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 80.10(0.110 g, Yield: 57.38%), MS (ES): m/z 650.28 [M+H]⁺.

Synthesis of Compound 80.11

Compound was synthesized using general procedure B to obtain 80.11.(0.070 g, Yield: 88.07%), MS (ES): m/z 470.19 [M+H]⁺.

Synthesis of Compound 1-83

Compound was synthesized using general procedure C to obtain I-83 (0.050g, Yield: 62.38%), MS (ES): 538.68 [M+H]⁺ LCMS purity: 97.72%, HPLCpurity: 97.02%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.87 (s, 1H), 11.24 (s, 1H),8.41-8.40 (d, J=4.4 Hz, 1H), 8.34 (s, 1H), 7.36 (s, 1H), 7.27-7.24 (t,J=10.8 Hz, 1H), 7.19 (bs, 2H), 6.84 (bs, 1H), 3.87 (s, 3H), 3.28-3.27(d, J=2.8 Hz, 3H), 2.85-2.84 (d, J=4.4 Hz, 3H), 2.43-2.35 (m, 2H), 1.24(bs, 2H), 0.94-0.86 (m, 4H).

Example 81:7-(cyclopropanecarboxamido)-2-(3-(8,8-dimethyl-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)-2-fluorophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-84)

Synthesis of Compound 81.2

To the solution of compound 81 (25.0 g, 165.56 mmol, 1.0 eq) indichloromethane (250 mL) was added triethylamine (35 mL, 248.34 mmol,1.5 eq) at 0° C. Reaction mixture was stirred at 0° C. for 15 min. Thencompound 81.1 (37.9 g, 165.56 mmol, 1.0 eq) was added dropwise at 0° C.and reaction mixture was stirred at 0° C. for 14 h. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with dichloromethane. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 27% ethyl acetate inhexane to obtain 81.2. (10.0 g, Yield: 20.15%). MS(ES): m/z 301.05[M+H]⁺.

Synthesis of Compound 81.3

To the solution of compound 81.2 (25.0 g, 83.33 mmol, 1.0 eq) inIsopropyl alcohol (250 mL) was added Potassium tert-butoxide solution(1M in tetrahydrofuran, 249 mL, 249.99 mmol, 3.0 eq) at 0° C. Reactionmixture was stirred at 0° C. for 30 min. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 25% ethyl acetate inhexane to obtain 81.3 (8.0 g, Yield: 43.81%). MS(ES): m/z 220.13 [M+H]⁺.

Synthesis of Compound 81.4

To the solution of compound 81.3 (8.0 g, 36.52 mmol, 1.0 eq) in toluene(80 mL) was added Triflic acid (12.8 mL, 146.08 mmol, 4.0 eq). Reactionmixture was irradiated at 210° C. in microwave for 15 min. Aftercompletion of reaction, reaction mixture was neutralized with methanolicammonia and concentrated to obtain crude material which was purified bycolumn chromatography and the compound was eluted in 2.0% methanol indichloromethane to obtain 81.4. (2.0 g, Yield: 42.44%). MS(ES): m/z130.08 [M+H]⁺.

Synthesis of Compound 81.5

To the solution of compound 81.4 (1.0 g, 7.75 mmol, 1.0 eq) intetrahydrofuran (30 mL) was added Lawesson's reagent (1.56 g, 3.87 mmol,0.5 eq). Reaction mixture was refluxed at 70° C. for 16 h. Aftercompletion of reaction, reaction mixture was transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by column chromatography and the compound was eluted in 15%ethyl acetate in hexane to obtain 81.5. (0.640 g, Yield: 56.92%).MS(ES): m/z 146.06 [M+H]⁺.

Synthesis of Compound 81.6

To the solution of compound 81.5 (0.640 g, 4.41 mmol, 1.0 eq) indichloromethane (15 mL) was added methyl iodide (0.688 g, 4.85 mmol, 1.1eq). Reaction mixture was stirred at room temperature for 15 h. Aftercompletion of reaction, reaction mixture was filtered and solid waswashed with dichloromethane. The obtained solid material was dissolvedwith 50% aqueous potassium carbonate solution (15 mL) and extracted withdichloromethane. Organic layer was combined, dried over sodium sulfateand concentrated under reduced pressure to obtain 81.6 (0.280 g, Yield:39.90%). MS(ES): m/z 160.08 [M+H]⁺.

Synthesis of Compound 81.7

To the solution of compound 81.6 (0.280 g, 1.76 mmol, 1.0 eq) in ethanol(9 mL) was added ammonium chloride (0.095 g, 1.76 mmol, 1.0 eq).Reaction mixture was refluxed for 1 h. After completion of reaction,reaction mixture was filtered through millipore and concentrated underreduced pressure to obtain 81.7 (0.265 g, Yield: 91.55%). MS(ES): m/z165.07 [M+H]⁺.

Synthesis of Compound 81.9

To the solution of compound 81.7 (0.265 g, 1.61 mmol, 1.0 eq) and 81.8(0.474 g, 1.61 mmol, 1.0 eq) in Dimethylformamide (15 mL) was addedSodium carbonate (0.853 g, 8.05 mmol, 5.0 eq). Reaction mixture washeated at 80° C. for 16 h. After completion of reaction, reactionmixture was transferred into water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatography andthe compound was eluted in 20% ethyl acetate in hexane to obtain 81.9.(0.2 g, Yield: 38.21%). MS(ES): m/z 324.03 [M+H]⁺.

Synthesis of Compound 81.10

Compound was synthesized as per experimental protocol of core synthesisB to obtain 81.10 (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 81.11

Compound was synthesized using general procedure A to obtain 81.11(0.250 g, Yield: 56.20%), MS (ES): m/z 616.27 [M+H]⁺.

Synthesis of Compound 81.12

To a solution of compound 81.11 (0.250 g, 0.40 mmol, 1.0 eq) intetrahydrofuran (4 mL) were added N,N-Diisopropylethylamine (0.22 mL,1.2 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 1.0 mL, 2.0 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.6 mL, 1.2 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 81.12(0.180 g, Yield: 72.12%), MS (ES): m/z 614.28 [M+H]⁺.

Synthesis of Compound 81.13

Compound was synthesized using general procedure B to obtain 81.13(0.096 g, Yield: 75.46%), MS (ES): m/z 435.19 [M+H]⁺.

Synthesis of Compound I-84

Compound was synthesized using general procedure C to obtain I-84 (0.050g, Yield: 45.03%), MS (ES): 503.46 [M+H]⁺ LCMS purity: 100%, HPLCpurity: 97.20%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.98 (s, 1H), 11.30 (s, 1H),8.40-8.39 (d, J=4 Hz, 1H), 8.33 (s, 1H), 8.12-8.08 (t, J=6.8 Hz, 1H),7.78-7.74 (m, 1H), 7.60-7.59 (d, J=4.4 Hz, 1H), 7.49 (s, 1H), 7.42-7.38(d, J=7.6 Hz, 1H), 4.16-4.01 (m, 4H), 2.87-2.86 (d, J=4.4 Hz, 3H), 2.27(bs, 1H), 1.57 (s, 6H), 0.90-0.80 (m, 4H).

Example 82:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-85)

Synthesis of Compound 82.2

To a solution of 82 (1.0 g, 5.23 mmol, 1.0 eq) and 82.1 (3.4 g, 20.92mmol, 4.0 eq) in Acetonitrile (25 mL) was added cesium carbonate (6.7 g,20.92 mmol, 4.0 eq). Reaction mixture was heated to refluxed at 80° C.for 18 h. After completion of reaction, reaction mixture was cooled toroom temperature, transferred into water and product was extracted withethyl acetate. Organic layer was combined, washed with brine solution,dried over sodium sulfate and concentrated under reduced pressure toobtain crude material. This was further purified by columnchromatography and the compound was eluted in 9% ethyl acetate in hexaneto obtain 82.2. (0.450 g, Yield: 31.24%), MS (ES): m/z 275.1 [M+H]⁺.

Synthesis of Compound 82.3

Compound was synthesized as per experimental protocol of core synthesisB to obtain 82.3 (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 82.4

Compound was synthesized using general procedure A to obtain 82.4 (0.190g, Yield: 46.49%), MS (ES): m/z 566.2 [M+H]⁺.

Synthesis of Compound 82.5

To a solution of compound 82.4 (0.190 g, 0.33 mmol, 1.0 eq) intetrahydrofuran (2 mL) were added N,N-Diisopropylethylamine (0.18 mL,0.99 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.82 mL, 1.65mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.49 mL, 0.99mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred to icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 82.5(0.160 g, Yield: 84.36%), MS (ES): m/z 565.26 [M+H]⁺.

Synthesis of Compound 82.6

Compound was synthesized using general procedure B to obtain 82.6 (0.083g, Yield: 76.20%), MS (ES): m/z 385.16 [M+H]⁺.

Synthesis of Compound I-85

Compound was synthesized using general procedure C to obtain I-85 (0.030g, Yield: 30.71%), MS (ES): 453.47 [M+H]⁺ LCMS purity: 96.20%, HPLCpurity: 95.70%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.06 (s, 1H), 11.30 (s, 1H),8.37-8.36 (d, J=4 Hz, 1H), 8.30 (s, 1H), 7.50-7.47 (t, J=6.8 Hz, 1H),7.43 (s, 1H), 7.36-7.32 (t, J=8 Hz, 1H), 7.28-7.24 (t, J=8 Hz, 1H),4.69-4.67 (m, 1H), 3.89-3.87 (m, 2H), 3.51-3.47 (t, J=9.6 Hz, 2H),2.84-2.83 (d, J=4 Hz, 3H), 2.24 (bs, 1H), 2.03-2.00 (m, 2H), 1.67-1.64(m, 2H), 0.98-0.93 (m, 4H).

Example 83:7-(cyclopropanecarboxamido)-2-(2-fluoro-4-(1-methyl-1H-imidazol-2-yl)-6-morpholinophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-86)

Synthesis of Compound 83.1

To a solution of 83 (2.0 g, 8.47 mmol, 1.0 eq) in N-Methyl-2-pyrrolidone(20 mL) was added Morpholine (0.884 g, 10.16 mmol, 1.2 eq). Reactionmixture was stirred at room temperature for 16 h. After completion ofreaction, reaction mixture was cooled to room temperature, transferredinto water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and the compound was eluted in20% ethyl acetate in hexane to obtain 83.1. (1.6 g, Yield: 62.40%), MS(ES): m/z 305.1 [M+H]⁺.

Synthesis of Compound 83.2

To a degassed solution of 83.1 (1.4 g, 4.59 mmol, 1.0 eq) andhexamethylditin (6.0 g, 18.36 mmol, 4.0 eq) in toluene (15 mL) was addedTetrakis(triphenylphosphine)palladium(0) (0.530 g, 0.45 mmol, 0.1 eq)and the reaction mixture was heated at 110° C. for 1 h under N₂. Aftercompletion of reaction, reaction mixture was concentrated under reducedpressure to obtain crude residue which was purified by columnchromatography using 5% ethyl acetate in hexane as eluant to obtain pure83.2. (0.7 g, Yield: 39.21%). MS(ES): m/z 390.0 [M+H]⁺.

Synthesis of Compound 83.4

To a degassed solution of 83.2 (0.7 g, 1.79 mmol, 1.0 eq) in toluene (14mL) was added 83.3 (0.344 g, 2.14 mmol, 1.2 eq). The reaction mixturewas degassed for 15 min under argon atmosphere, thenTetrakis(triphenylphosphine)palladium(0) (0.103 g, 0.089 mmol, 0.05 eq)was added and again degassed for 5 min. Reaction mixture was heated torefluxed at 110° C. for 16 h under N₂. After completion of reaction,reaction mixture was concentrated under reduced pressure to obtain cruderesidue which was purified by column chromatography using 6% ethylacetate in hexane as eluant to obtain pure 83.4. (0.320 g, Yield:58.06%). MS(ES): m/z 307.12 [M+H]⁺.

Synthesis of Compound 83.5

To a solution of 83.4 (0.320 g, 1.04 mmol, 1.0 eq) in methanol (6 ml),was added 10% palladium on charcoal (0.2 g). Hydrogen was purged throughreaction mixture for 4 h at room temperature. After completion ofreaction, reaction mixture was filtered through Celite-bed and washedwith methanol. Filtrate was concentrated under reduced pressure toobtain crude material. This was further purified by trituration withn-pentane to obtain pure 83.5 (0.260 g, Yield: 90.07%). MS (ES): m/z277.14 [M+H]⁺.

Synthesis of Compound 83.6

To a solution of compound 83.5 (0.520 g, 1.88 mmol, 1.0 eq) inacetonitrile (6 mL) was added tert-Butyl nitrite (0.387 g, 3.76 mmol,2.0 eq) and reaction mixture was cooled to 0° C. Then Copper (II)bromide (0.838 g, 3.76 mmol, 2.0 eq) was added dropwise into thereaction mixture. The reaction was stirred at room temperature for 2 h.After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by combi flash using 20% ethyl acetate in hexane aseluant to obtain pure 83.6. (0.280 g, Yield: 43.74%). MS(ES): m/z 340.2[M+H]⁺.

Synthesis of Compound 83.7

Compound was synthesized as per experimental protocol of core synthesisB to obtain 83.7 (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 83.8

Compound was synthesized using general procedure A to obtain 83.8 (0.142g, Yield: 46.74%), MS (ES): m/z 631.28 [M+H]⁺.

Synthesis of Compound 83.9

To a solution of compound 83.8 (0.142 g, 0.22 mmol, 1.0 eq) intetrahydrofuran (2 mL) were added N,N-Diisopropylethylamine (0.12 mL,0.66 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.55 mL, 1.1 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.33 mL, 0.66 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred to ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 83.9(0.102 g, Yield: 71.94%), MS (ES): m/z 630.29 [M+H]⁺.

Synthesis of Compound 83.10

Compound was synthesized using general procedure B to obtain 83.10(0.070 g, Yield: 96.15%), MS (ES): m/z 450.20 [M+H]⁺.

Synthesis of compound I-86

Compound was synthesized using general procedure C to obtain I-86 (0.032g, Yield: 39.70%), MS (ES): 518.51 [M+H]⁺ LCMS purity: 99.07%, HPLCpurity: 98.16%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.29 (s, 1H), 11.41 (s, 1H),8.41-8.40 (d, J=4.4 Hz, 1H), 8.30 (s, 1H), 7.42 (bs, 2H), 7.34 (bs, 1H),7.05 (s, 1H), 6.82 (s, 1H), 3.86 (bs, 3H), 3.67 (bs, 3H), 2.83-2.82 (d,J=3.6 Hz, 3H), 1.54 (bs, 3H), 1.22 (bs, 3H), 1.00-0.95 (m, 4H).

Example 84:7-(cyclopropanecarboxamido)-2-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-2-fluorophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-87)

Synthesis of Compound 84.2

To a cooled solution of 84 (2.0 g, 8.43 mmol, 1.0 eq) in dichloromethane(20 mL) was added dropwise 84.1 (1.8 g, 21.07 mmol, 2.5 eq) dissolved indichloromethane (20 mL) over 30 min. Reaction mixture was stirred atroom temperature for 16 h. After completion of reaction, reactionmixture was concentrated under reduced pressure, basified with 5MPotassium hydroxide solution and extracted with dichloromethane. Organiclayer was combined, dried over sodium sulfate and concentrated underreduced pressure to obtain crude material. This was further purified bycolumn chromatography and the compound was eluted in 5% ethyl acetate inhexane to obtain 84.2 (0.172 g, Yield: 7.50%), MS (ES): m/z 273.0[M+H]⁺.

Synthesis of Compound 84.3

Compound was synthesized as per experimental protocol of core synthesisB to obtain 84.3 (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 84.4

Compound was synthesized using general procedure A to obtain 84.4 (0.142g, Yield: 52.40%), MS (ES): m/z 563.2 [M+H]⁺.

Synthesis of Compound 84.5

To a solution of compound 84.4 (0.142 g, 0.25 mmol, 1.0 eq) intetrahydrofuran (2 mL) were added N,N-Diisopropylethylamine (0.13 mL,0.75 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.62 mL, 1.25mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.37 mL, 0.75mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 84.5(0.088 g, Yield: 62.08%), MS (ES): m/z 562.26 [M+H]⁺.

Synthesis of Compound 84.6

Compound was synthesized using general procedure B to obtain 84.6 (0.040g, Yield: 98.17%), MS (ES): m/z 382.16 [M+H]⁺.

Synthesis of Compound I-87

Compound was synthesized using general procedure C to obtain I-87 (0.025g, Yield: 51.74%), MS (ES): 450.66 [M+H]⁺ LCMS purity: 95.00%, HPLCpurity: 98.19%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.21 (s, 1H), 11.44 (s, 1H),8.42-8.41 (d, J=4 Hz, 1H), 8.30 (s, 1H), 7.89 (bs, 1H), 7.51 (bs, 1H),7.07 (bs, 1H), 6.82 (bs, 1H), 4.14 (bs, 2H), 2.85-2.84 (d, J=4 Hz, 3H),1.54 (bs, 1H), 1.33 (s, 6H), 1.00-0.93 (m, 4H).

Example 85:(S)-7-(cyclopropanecarboxamido)-2-(2-fluoro-4-((tetrahydrofuran-2-yl)methoxy)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-88)

Synthesis of Compound 85.2

To a solution of 85 (2.0 g, 10.47 mmol, 1.0 eq) and 85.1 (1.3 mL, 12.56mmol, 1.2 eq) in tetrahydrofuran (25 mL) was added Triphenylphosphine(3.4 g, 13.08 mmol, 1.25 eq) and the reaction mixture was stirred for 5min. Then Diisopropyl azodicarboxylate (2.4 mL, 12.56 mmol, 1.2 eq) wasadded dropwise and the reaction mixture was stirred at room temperaturefor 16 h. After completion of reaction, reaction mixture wasconcentrated under reduced pressure, 1N Sodium hydroxide solution wasadded, and extracted with dichloromethane. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by 6% ethyl acetate in hexane to obtain 85.2. (0.9 g, Yield:31.24%), MS (ES): m/z 276.0 [M+H]⁺.

Synthesis of Compound 85.3

Compound was synthesized as per experimental protocol of core synthesisB to obtain 85.3 (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 85.4

Compound was synthesized using general procedure A to obtain 85.4 (0.190g, Yield: 39.85%), MS (ES): m/z 566.24 [M+H]⁺.

Synthesis of Compound 85.5

To a solution of compound 85.4 (0.190 g, 0.33 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.18 mL,0.99 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.82 mL, 1.65mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.49 mL, 0.99mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 85.5(0.132 g, Yield: 69.59%), MS (ES): m/z 565.26 [M+H]⁺.

Synthesis of Compound 85.6

Compound was synthesized using general procedure B to obtain 85.6 (0.070g, Yield: 77.90%), MS (ES): m/z 385.16 [M+H]⁺.

Synthesis of Compound I-88

Compound was synthesized using general procedure C to obtain I-88 (0.029g, Yield: 35.20%), MS (ES): 453.47 [M+H]⁺ LCMS purity: 100%, HPLCpurity: 100%, CHIRAL HPLC: 100%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.96 (s,1H), 11.27 (s, 1H), 8.35 (bs, 1H), 8.30 (bs, 1H), 7.90-7.85 (t, J=8.4Hz, 1H), 7.34 (bs, 1H), 7.09-7.06 (d, J=12.5 Hz, 1H), 6.98 (bs, 1H),4.19 (bs, 1H), 4.07-3.98 (m, 2H), 3.80 (bs, 1H), 3.69 (bs, 1H),2.85-2.84 (d, J=3.8 Hz, 3H), 2.25 (bs, 1H), 2.02-2.00 (m, 1H), 1.86 (bs,2H), 1.69 (bs, 1H), 0.98-0.93 (m, 4H).

Example 86:2-(4-(1,4-dioxan-2-yl)-2-methoxyphenyl)-7-(cyclopropanecarboxamido)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-89)

Synthesis of Compound 86.1

To a solution of 86 (3.0 g, 14.15 mmol, 1.0 eq) in dichloromethane (35mL) was added Diisobutylaluminium hydride (1M in toluene, 28 mL, 28.3mmol, 2.0 eq) dropwise at −78° C. Reaction mixture was stirred at roomtemperature for 5 h. After completion of reaction, methanol and 1Nhydrochloric acid were added to it, stirred at 0° C. for 15 min andextracted with dichlromethane. Organic layer was combined, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial, which was purified by 12% ethyl acetate in hexane to obtain86.1. (1.6 g, Yield: 52.59%), MS (ES): m/z 215.9 [M+H]⁺.

Synthesis of Compound 86.2

A solution of Sodium hydride (0.267 g, 11.16 mmol, 1.5 eq) in Dimethylsulfoxide (15 mL) was heated at 70° C. for 2 h. The reaction mixture wascooled to 0° C. and tetrahydrofuran (16 mL) and Trimethylsulfoniumiodide (2.2 g, 11.16 mmol, 1.5 eq) were added. The reaction mixture wasstirred at 0° C. for 10 min. After 10 min, 86.1 (1.6 g, 7.44 mmol, 1.0eq) was added and stirred at room temperature for 5 h. After completionof reaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by 15%ethyl acetate in hexane to obtain 86.2 (0.950 g, Yield: 55.74%), MS(ES): m/z 229.9 [M+H]⁺.

Synthesis of Compound 86.3

To the solution of 86.2 (0.950 g, 4.14 mmol, 1.0 eq) in Ethylene glycol(10 mL) was added concentrated sulfuric acid (1 mL), and the reactionwas heated at 135° C. for 2 h. After completion, reaction mixture wastransferred into water and product was extracted with ethyl acetate.Organic layer was combined, washed with brine solution, dried oversodium sulfate and concentrated under reduced pressure to obtain crudematerial. This was further purified by 20% ethyl acetate in hexane toobtain 86.3 (0.160 g, Yield: 14.13%), MS (ES): m/z 273.1 [M+H]⁺.

Synthesis of Compound 86.4

Compound was synthesized as per experimental protocol of core synthesisB to obtain 86.4 (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 86.5

Compound was synthesized using general procedure A to obtain 86.5 (0.470g, Yield: 57.71%), MS (ES): m/z 563.2 [M+H]⁺.

Synthesis of Compound 86.6

To a solution of compound 86.5 (0.470 g, 0.83 mmol, 1.0 eq) intetrahydrofuran (5 mL) were added N,N-Diisopropylethylamine (0.45 mL,2.49 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 2.07 mL, 4.15mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 1.24 mL, 2.49mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 86.6(0.370 g, Yield: 78.86%), MS (ES): m/z 562.2 [M+H]⁺.

Synthesis of Compound 86.7

To a solution of 86.6 (0.370 g, 0.65 mmol, 1.0 eq) in methanol (10 mL)was added 20% palladium hydroxide on carbon (0.4 g). Hydrogen was purgedthrough reaction mixture for 12 h at room temperature. After completion,reaction mixture was filtered through Celite-bed and washed withmethanol. Filtrate was concentrated under reduced pressure to obtaincrude material. This was further purified by trituration with n-pentaneto obtain pure 86.7 (0.140 g, Yield: 55.67%), MS (ES): m/z 383.1 [M+H]⁺.

Synthesis of Compound I-89

Compound was synthesized using general procedure C to obtain I-89 (0.030g, Yield: 38.32%), MS (ES): 451.47 [M+H]⁺ LCMS purity: 97.44%, HPLCpurity: 95.11%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.58 (s, 1H), 11.39 (s, 1H),8.38 (bs, 1H), 8.22 (s, 1H), 7.91-7.89 (d, J=8 Hz, 1H), 7.42 (bs, 1H),7.14 (bs, 1H), 7.03-7.01 (d, J=7.6 Hz, 1H), 5.07-5.04 (d, J=5.2 Hz, 1H),3.93 (s, 2H), 3.83 (s, 2H), 3.80-3.77 (m, 2H), 2.96-2.94 (d, J=4.8 Hz,2H), 2.84-2.83 (d, J=4.4 Hz, 3H), 2.26 (bs, 1H), 1.22 (s, 1H), 1.01-0.93(m, 4H).

Example 87:(R)-7-(cyclopropanecarboxamido)-2-(2-fluoro-6-(3-methoxypyrrolidin-1-yl)-4-(1-methyl-1H-imidazol-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-90)

Synthesis of Compound 87.2

To a solution of 87 (5.0 g, 21.00 mmol, 1.0 eq) in dimethylformamide (70mL), was added 87.1 (2.3 g, 23.1 mmol, 1.1 eq). The reaction mixture wasdegassed for 10 min under argon atmosphere followed by addition ofpotassium carbonate (8.6 g, 63.0 mmol, 3.0 eq). The reaction mixture wasstirred at room temperature for 10 h. After completion of reaction,reaction mixture was transferred into ice cold water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by 5% ethylacetate in hexane to obtain 87.2 (4.2 g, Yield: 62.64%). MS (ES): m/z318.0 [M+H]⁺.

Synthesis of Compound 87.3

To a solution of 87.2 (4.2 g, 13.16 mmol, 1.0 eq) in methanol were addedAcetic acid (7.5 mL, 131.6 mmol, 10.0 eq) and Iron powder (3.6 g, 65.8mmol, 5.0 eq) Reaction mixture was stirred at 90° C. for 30 min. Aftercompletion of reaction, reaction mixture was cooled to room temperatureand filtered through Celite-bed. Filtrate was concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 10% ethyl acetate inhexane to obtain 87.3 (3.6 g, Yield: 94.60%), MS (ES): m/z 289.15[M+H]⁺.

Synthesis of Compound 87.4

To a solution of 87.3 (3.6 g, 12.45 mmol, 1.0 eq) in 1,4-dioxane (60 mL)was added Bis(pinacolato)diboron (3.4 g, 13.69 mmol, 1.1 eq), andPotassium acetate (3.6 g, 37.35 mmol, 3.0 eq). The reaction mixture wasdegassed for 15 min under argon atmosphere, thenTris(dibenzylideneacetone)dipalladium(0) (0.796 g, 0.87 mmol, 0.07 eq)and 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.592 g, 1.24mmol, 0.1 eq) were added, and degassed for 5 min. The reaction mixturewas stirred at 110° C. for 4 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 12% ethyl acetate in hexane as eluant toobtain pure 87.4. (2.9 g, Yield: 69.28%). MS(ES): m/z 336.2 [M+H]⁺.

Synthesis of Compound 87.6

Argon was purged for 15 min through a stirred solution of 87.4 (2.9 g,8.63 mmol, 1.0 eq) and 87.5 (1.8 g, 11.21 mmol, 1.3 eq) indimethylformamide (30 mL). Bis(triphenylphosphine)palladium(II)dichloride (0.605 g, 0.86 mmol, 0.1 eq) was added and was further purgedfor 10 min. Reaction was allowed to stir at 60° C. for 5 h. Aftercompletion, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain 87.6 (1.67 g, Yield: 66.68%). MS (ES): m/z 291.15[M+H]⁺.

Synthesis of Compound 87.7

To compound 87.6 (0.6 g, 2.06 mmol, 1.0 eq) was added 30% Hydrobromicacid (1.2 mL) dropwise at 0° C. Sodium nitrite (0.284 g, 4.12 mmol, 2.0eq) and acetone (4.8 mL) were added and the reaction mixture was stirredfor 2 min. Copper(I) bromide (0.589 g, 4.12 mmol, 2.0 eq) was added andreaction mixture stirred for 2 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain 87.7. (0.090 g, Yield: 12.29%). MS(ES):m/z 354.2 [M+H]⁺.

Synthesis of Compound 87.8

Compound was synthesized as per experimental protocol of core synthesisB to obtain 87.8 (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺

Synthesis of Compound 87.9

Compound was synthesized using general procedure A to obtain 87.9.(0.055 g, Yield: 35.42%), MS (ES): m/z 645.29 [M+H]⁺.

Synthesis of Compound 87.10

To a solution of compound 87.9 (0.055 g, 0.085 mmol, 1.0 eq) intetrahydrofuran (5 mL) were added N,N-Diisopropylethylamine (0.046 mL,0.25 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.21 mL, 0.42mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.12 mL, 0.25mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 87.10(0.047 g, Yield: 85.59%), MS (ES): m/z 643.7 [M+H]⁺.

Synthesis of Compound 87.11

Compound was synthesized using general procedure B to obtain 87.11(0.033 g, Yield: 97.52%), MS (ES): m/z 464.2 [M+H]⁺.

Synthesis of Compound I-90

Compound was synthesized using general procedure C to obtain I-90 (0.028g, Yield: 62.60%), MS (ES): 532.52 [M+H]⁺ LCMS purity: 99.64%, HPLCpurity: 98.04%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.67 (s, 1H), 11.16 (s, 1H),8.36 (bs, 1H), 8.32 (s, 1H), 7.46 (s, 1H), 7.23 (bs, 1H), 7.06-7.03 (d,J=7.6 Hz, 2H), 6.82-6.81 (d, J=6.8 Hz, 1H), 5.34 (bs, 2H), 4.45 (bs,2H), 4.09 (bs, 2H), 3.99-3.94 (m, 3H), 3.86 (s, 3H), 2.83-2.82 (d, J=4.4Hz, 3H), 1.85 (bs, 1H), 1.54 (bs, 1H), 0.90-0.88 (m, 4H).

Example 88:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-((1s,3s)-3-methoxycyclobutyl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-91)

Synthesis of Compound 88.1

A solution of Methyl triphenyl phosphonium iodide (24.8 g, 61.57 mmol,2.5 eq) in tetrahydrofuran (150 mL) was cooled to 0° C. Potassiumtert-butoxide (6.8 g, 61.57 mmol, 2.5 eq) was added portionwise over 15min. After 10 min, 88 (5.0 g, 24.63 mmol, 1.0 eq) was dissolved intetrahydrofuran (20 mL) and added dropwise over 15 min. Reaction mixturewas stirred at room temperature for 1 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by 2% ethylacetate in hexane to obtain 88.1 (2.6 g, Yield: 52.51%), MS (ES): m/z201.04 [M+H]⁺.

Synthesis of Compound 88.2

A solution of Dimethylacetamide (1.2 g, 14.22 mmol, 1.1 eq) in1,2-Dichloroethane (26 mL) was cooled to −12° C. Triflic anhydride (5.0g, 14.22 mmol, 1.1 eq) was added over 30 min. After 15 min, 88.1 (2.6 g,12.93 mmol, 1.0 eq) dissolved in 1,2-Dichloroethane (15 mL) was addedslowly. Then 2,4,6-Collidine (2.6 mL) was added to reaction mixture at−12° C. and stirred at 150° C. for 4 h. Then reaction mixture was cooledto room temperature, water was added and again heated to 80° C. for 16h. After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 6% ethyl acetate in hexane to obtain 88.2 (0.7 g,Yield: 22.27%), MS (ES): m/z 243.08 [M+H]⁺.

Synthesis of Compound 88.3

A solution of 88.2 (0.7 g, 2.88 mmol, 1.0 eq) in methanol (10 mL) wascooled to 0° C. and sodium borohydride (0.119 g, 3.16 mmol, 1.1 eq) wasadded portionwise. Reaction mixture was stirred at room temperature for1 h. After completion of reaction, reaction mixture was transferred intowater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 10% ethyl acetate in hexane to obtain 88.3 (0.630 g,Yield: 89.26%), MS (ES): m/z 245.9 [M+H]⁺.

Synthesis of Compound 88.4

To a cooled suspension of sodium hydride (60%) (0.032 g, 1.33 mmol, 1.5eq) in N,N-Dimethylformamide (4.4 mL) at 0° C. was added 88.3 (0.220 g,0.89 mmol, 1.0 eq) and Methyl iodide (0.150 g, 1.06 mmol, 1.2 eq).Reaction mixture was stirred at room temperature for 1 h. Aftercompletion of reaction, reaction mixture was transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by 10% ethyl acetate in hexane to obtain 88.4 (0.180 g, Yield:77.39%), MS (ES): m/z 259.12 [M+H]⁺.

Synthesis of Compound 88.5

Compound was synthesized as per experimental protocol of core synthesisB to obtain 88.5 (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 88.6

Compound was synthesized using general procedure A to obtain 88.6 (0.120g, Yield: 60.44%), MS (ES): m/z 550.2 [M+H]⁺.

Synthesis of Compound 88.7

To a solution of compound 88.6 (0.120 g, 0.21 mmol, 1.0 eq) intetrahydrofuran (2 mL) were added N,N-Diisopropylethylamine (0.11 mL,0.63 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.52 mL, 1.05mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.31 mL, 0.63mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 88.7(0.087 g, Yield: 72.63%), MS (ES): m/z 549.26 [M+H]⁺.

Synthesis of Compound 88.8

Compound was synthesized using general procedure B to obtain 88.8 (0.047g, Yield: 80.45%), MS (ES): m/z 369.1 [M+H]⁺.

Synthesis of Compound I-91

Compound was synthesized using general procedure C to obtain I-91 (0.025g, Yield: 44.90%), MS (ES): 437.46 [M+H]⁺ LCMS purity: 98.50%, HPLCpurity: 95.00%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.11 (s, 1H), 11.32 (s, 1H),8.43 (bs, 1H), 8.30 (s, 1H), 7.83 (bs, 1H), 7.38-7.35 (t, J=7.6 Hz, 1H),7.09-7.07 (d, J=7.2 Hz, 1H), 6.84 (s, 1H), 4.05-3.90 (m, 2H), 3.20 (s,3H), 2.86-2.85 (d, J=4.4 Hz, 3H), 2.00-1.97 (m, 2H), 1.56 (bs, 1H), 1.24(bs, 1H), 1.20-1.17 (t, J=7.2 Hz, 1H), 1.00-0.96 (m, 4H).

Example 89:7-(cyclopropanecarboxamido)-2-(7-fluoro-1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-92)

Synthesis of Compound 89.1

To a solution of 89 (2.0 g, 8.40 mmol, 1.0 eq) in N,N-dimethylformamide(20 mL) was added Potassium carbonate (2.3 g, 16.8 mmol, 2.0 eq). ThenMethylamine (2M in tetrahydrofuran, 5.04 mL, 10.08 mmol, 1.2 eq) wasadded and stirred at room temperature for 5 h. After completion ofreaction, reaction mixture was filtered and concentrated under reducedpressure to obtain 89.1 (1.2 g, Yield: 57.34%), MS (ES): m/z 249.0[M+H]⁺.

Synthesis of Compound 89.2

To a solution of 89.1 (1.2 g, 4.81 mmol, 1.0 eq) in 1,4 Dioxane (15 mL)was added stannous chloride dihydrate (5.4 g, 24.05 mmol, 5.0 eq). Thenhydrochloric acid (1.2 mL) was added to the reaction mixture and stirredat room temperature for 16 h. After completion of reaction, reactionmixture was transferred into water, added 1N sodium hydroxide solutionand product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by trituration with n-pentane to obtain 89.2 (0.7 g,Yield: 66.32%), MS (ES): m/z 219.06 [M+H]⁺.

Synthesis of Compound 89.3

A solution of 89.2 (0.7 g, 3.19 mmol, 1.0 eq) in Acetic acid (10 mL) washeated at 130° C. for 4 h. After completion of reaction, reactionmixture was transferred into saturated Sodium bicarbonate solution,filtered and concentrated under reduced pressure to obtain 89.3 (0.350g, Yield: 45.06%), MS (ES): m/z 243.0 [M+H]⁺.

Synthesis of Compound 89.4

Compound was synthesized as per experimental protocol of core synthesisB to obtain 89.4 (Yield: 66.51%), MS (ES): m/z 416.17 [M+H]⁺.

Synthesis of Compound 89.5

Compound was synthesized using general procedure A to obtain 89.5 (0.2g, Yield: 51.88%), MS (ES): m/z 534.2 [M+H]⁺.

Synthesis of Compound 89.6

To a solution of compound 89.5 (0.2 g, 0.37 mmol, 1.0 eq) intetrahydrofuran (2 mL) were added N,N-diisopropylethylamine (0.2 mL,1.11 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.92 mL, 1.85mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.55 mL, 1.11mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain 89.6.(0.122 g, Yield: 61.11%), MS (ES): m/z 533.2 [M+H]⁺.

Synthesis of Compound 89.7

Compound was synthesized using general procedure B to obtain 89.7 (0.052g, Yield: 64.63%), MS (ES): m/z 353.15 [M+H]⁺.

Synthesis of Compound I-92

Compound was synthesized using general procedure C to obtain I-92 (0.025g, Yield: 40.29%), MS (ES): 421.51 [M+H]⁺ LCMS purity: 95.65%, HPLCpurity: 95.00%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.10 (s, 1H), 11.35 (s, 1H),8.35 (bs, 1H), 8.29 (s, 1H), 7.67-7.65 (d, J=7.6 Hz, 1H), 7.50-7.48 (d,J=8.4 Hz, 1H), 7.41 (s, 1H), 3.96 (s, 3H), 2.85-2.83 (d, J=4.4 Hz, 3H),2.55 (s, 3H), 1.14-1.11 (t, J=7.2 Hz, 1H), 0.98-0.86 (m, 4H).

Example 90:—N-methyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-phenyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-93)

Synthesis of Compound 90

Compound was synthesized as per experimental protocol I-1 to obtain 90.MS (ES): m/z 268.10 [M+H]⁺.

Synthesis of Compound 90.1

To a solution of compound 90 (0.4 g, 1.49 mmol, 1.0 eq) indichloromethane (5 mL) was added tert-Butyl nitrite (0.168 g, 1.63 mmol,1.1 eq) and Copper(II) bromide (0.166 g, 0.74 mmol, 0.5 eq). Thereaction mixture was stirred at room temperature for 2 h. Aftercompletion of reaction, reaction mixture was transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain 90.1. (0.150 g, Yield: 24.44%). MS(ES):m/z 410.07 [M+H]⁺.

Synthesis of Compound 90.3

To a solution of 90.1 (0.150 g, 0.36 mmol, 1.0 eq) in 1,4-dioxane (5 mL)was added 90.2 (0.042 g, 0.43 mmol, 1.2 eq), and potassium carbonate(0.1 g, 0.73 mmol, 2.0 eq). The reaction mixture was degassed for 10min. under argon atmosphere, thentris(dibenzylideneacetone)dipalladium(0) (0.016 g, 0.018 mmol, 0.05 eq)and −4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.021 g, 0.036mmol, 0.1 eq) were added, and degassed for 5 min. The reaction wasstirred at 70° C. for 4 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 2.3% methanol in dichloromethane as eluantto obtain pure 90.2 (0.064 g, Yield: 50.37%). MS(ES): m/z 348.14 [M+H]⁺.

Synthesis of Compound I-93

To a solution of compound 90.2 (0.064 g, 0.18 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.09 mL,0.54 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.45 mL, 0.9 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.27 mL, 0.54 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred into ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by combi flash using 2.5% methanol in dichloromethaneto obtain I-93 (0.028 g, Yield: 43.87%), MS (ES): m/z 347.39 [M+H]⁺,LCMS purity: 99.38%, HPLC purity: 98.44%, ¹H NMR (DMSO-d₆, 400 MHZ):11.79 (s, 1H), 9.60 (bs, 1H), 8.19 (s, 1H), 8.08-8.07 (d, J=4.4 Hz, 1H),7.87-7.86 (d, J=7.2 Hz, 2H), 7.59-7.52 (m, 3H), 7.42-7.39 (m, 1H), 7.31(s, 1H), 6.84 (s, 1H), 3.79 (s, 3H), 2.82-2.81 (d, J=4 Hz, 3H).

Example 91:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-((1r,3r)-3-methoxycyclobutyl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-94)

Synthesis of Compound 91

Compound was synthesized as per experimental protocol I-91 to obtain 91(Yield: 89.26%). MS (ES): m/z 245.9 [M+H]⁺.

Synthesis of Compound 91.1

To a solution of 91 (0.5 g, 2.04 mmol, 1.0 eq) and 4-nitrobenzoic acid(0.681 g, 4.08 mmol, 2.0 eq) in tetrahydrofuran (10 mL) was addedtriphenylphosphine (1.6 g, 6.12 mmol, 3.0 eq) and Diisopropylazodicarboxylate (1.2 g, 6.12 mmol, 3.0 eq) at 0° C. The reactionmixture was stirred at room temperature for 6 h. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and the compound was eluted in 20% ethyl acetate inhexane to obtain 91.1 (0.5 g, Yield: 90.08%). MS(ES): m/z 394.2 [M+H]⁺.

Synthesis of Compound 91.2

To a solution of 91.1 (0.5 g, 1.26 mmol, 1.0 eq), intetrahydrofuran:methanol:water (16 mL, 2:1) was added lithium hydroxide(0.264 g, 6.3 mmol, 5.0 eq). The reaction was stirred at roomtemperature for 16 h. After completion of reaction, reaction mixture wasconcentrated under reduced pressure to obtain residue. To this was addedwater and was acidified with 1N hydrochloric acid to adjust pH-6-6.5 at10° C. Product was extracted with dichloromethane. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and compound was eluted in2.1% methanol in dichloromethane to obtain pure 91.2 (0.230 g, Yield:73.98%). MS(ES): m/z 245.09 [M+H]⁺.

Synthesis of Compound 91.3

To a solution of 91.2 (0.205 g, 0.83 mmol, 1.0 eq) inN,N-Dimethylformamide (4 mL), was added portionwise sodium hydride (0.04g, 1.66 mmol, 2 eq) at 0° C. and stirred for 20 min. Methyl iodide(0.130 g, 0.91 mmol, 1.1 eq) was added and reaction mixture was stirredat room temperature for 2 h. After completion of reaction, reactionmixture was transferred into ice, stirred and extracted with diethylether. Organic layer was combined, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by column chromatography and compound was eluted in1.2% methanol in dichloromethane to obtain pure 91.3 (0.143 g, Yield:65.98%). MS (ES): m/z 259.1 [M+H]⁺.

Synthesis of Compound 91.4

Compound was synthesized as per experimental protocol of core synthesisto obtain 91.4 (Yield: 66.51%). MS (ES): m/z 416.1 [M+H]⁺.

Synthesis of Compound 91.5

Compound was synthesized using general procedure A to obtain 91.5 (0.122g, Yield: 36.87%), MS (ES): m/z 550.2 [M+H]⁺.

Synthesis of Compound 91.6

To a solution of compound 91.5 (0.122 g, 0.22 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.12 mL,0.66 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.55 mL, 1.1 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.33 mL, 0.66 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred into ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.2% methanol in dichloromethane to obtain 91.6(0.106 g, Yield: 87.04%), MS (ES): m/z 549.2 [M+H]⁺.

Synthesis of Compound 91.7

Compound was synthesized using general procedure B to obtain 91.7 (0.070g, Yield: 98.35%), MS (ES): m/z 369.1 [M+H]⁺.

Synthesis of Compound I-94

Compound was synthesized using general procedure C to obtain I-94 (0.025g, Yield: 30.14%), MS (ES): m/z 437.52 [M+H]⁺, LCMS purity 96.87%, HPLCpurity: 97.70%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.99 (s, 1H), 11.29 (s, 1H),8.38-8.37 (d, J=4.8 Hz, 1H), 8.31 (s, 1H), 7.82-7.78 (t, J=6.8 Hz, 1H),7.54-7.50 (t, J=7.2 Hz, 1H), 7.44 (bs, 1H), 7.38-7.34 (t, J=8 Hz, 1H),4.07-4.04 (m, 1H), 3.86-3.82 (m, 1H), 3.21 (s, 3H), 3.85-3.84 (d, J=4Hz, 3H), 2.44-2.40 (m, 3H), 2.26 (bs, 1H), 0.99-0.94 (m, 3H), 0.87 (bs,2H).

Example 92:7-(cyclopropanecarboxamido)-2-(2-fluoro-3-(tetrahydrofuran-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-95)

Synthesis of Compound 92.1

To a solution of compound 92 (5.0 g, 22.72 mmol, 1.0 eq) in 1,4-dioxane(25 ml) was added 2,3-dihydrofuran (7.9 g, 113.6 mmol, 5.0 eq) andN,N-Diisopropylethylamine (4.1 mL, 22.72 mmol, 1.0 eq). The reactionmixture was degassed for 10 min under argon atmosphere, thenBromo(tri-tert-butylphosphine)palladium(I) dimer (0.176 g, 0.22 mmol,0.01 eq) was added, and degassed for 5 min. The reaction was refluxed at120° C. for 6 h. After completion of reaction, reaction mixture wasfiltered through Celite-bed and washed with ethyl acetate. Filtrate wasconcentrated under reduced pressure to obtain crude material. This wasfurther purified by combi flash using 5% ethyl acetate in hexane aseluant to obtain pure 92.1 (2.7 g, Yield: 56.79%). MS(ES): m/z209.05[M+H]⁺.

Synthesis of Compound 92.2

Palladium hydroxide on carbon (20%, 0.6 g) was added to a solution of92.1 (2.7 g, 12.91 mmol, 1.0 eq) in methanol (30 mL). Then Triethylamine(1.86 mL, 12.91 mmol, 1.0 eq) was added to the reaction mixture andhydrogen was purged through reaction mixture for 5 h at roomtemperature. After completion of reaction, reaction mixture was filteredthrough Celite-bed and washed with methanol. Filtrate was concentratedunder reduced pressure to obtain crude material. This was furtherpurified by trituration with n-pentane to obtain pure 92.2 (0.8 g,Yield: 34.20%). MS (ES): m/z 181.09 [M+H]⁺.

Synthesis of Compound 92.3

To a solution of compound 92.2 (0.8 g, 4.41 mmol, 1.0 eq) inacetonitrile (10 ml) was added copper(II) bromide (4.9 g, 22.05 mmol,5.0 eq) and tert-butyl nitrite (0.908 g, 8.82 mmol, 2.0 eq). Thereaction was stirred at room temperature for 2 h. After completion ofreaction, reaction mixture was transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain 92.3 (0.730 g, Yield: 67.47%). MS(ES): m/z 245.09[M+H]⁺.

Synthesis of Compound 92.4

Compound was synthesized as per experimental protocol of core synthesisB to obtain 92.4 (Yield: 66.51%). MS (ES): m/z 416.1 [M+H]⁺.

Synthesis of Compound 92.5

Compound was synthesized using general procedure A to obtain 92.5 (0.165g, Yield: 25.58%), MS (ES): m/z 535.2 [M+H]⁺.

Synthesis of Compound 92.6

To a solution of compound 92.5 (0.165 g, 0.30 mmol, 1.0 eq) intetrahydrofuran (5 mL) were added N,N-Diisopropylethylamine (0.16 mL,0.9 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.75 mL, 1.5 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.45 mL, 0.9 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h. Aftercompletion of reaction, reaction mixture was transferred into ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.3% methanol in dichloromethane to obtain 92.6(0.135 g, Yield: 81.97%). MS(ES): m/z 534.2 [M+H]⁺.

Synthesis of Compound 92.7

Compound was synthesized using general procedure B to obtain 92.7 (0.085g, Yield: 84.99%), MS (ES): m/z 355.1 [M+H]⁺.

Synthesis of Compound I-95

Compound was synthesized using general procedure C to obtain I-95 (0.013g, Yield: 12.83%), MS (ES): m/z 423.31 [M+H]⁺, LCMS purity: 96.60%, HPLCpurity: 97.82%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.01 (s, 1H), 11.29 (s, 1H),8.38-8.37 (d, J=4.8 Hz, 1H), 8.31 (s, 1H), 7.88-7.84 (t, J=7.2 Hz, 1H),7.53-7.49 (m, 1H), 7.45 (s, 1H), 7.38-7.34 (t, J=7.6 Hz, 1H), 5.18-5.15(t, J=6.8 Hz, 1H), 4.06-4.03 (m, 1H), 3.89-3.86 (m, 1H), 2.85-2.84 (d,J=4.4 Hz, 3H), 2.26 (bs, 1H), 2.01-1.96 (m, 2H), 1.79-1.74 (m, 1H), 1.24(s, 1H), 0.96-0.94 (m, 4H).

Example 93:7-(cyclopropanecarboxamido)-N-methyl-2-(piperidin-1-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-96)

Synthesis of Compound 93

Compound was synthesized as per experimental protocol of core synthesisA to obtain 93. (Yield: 79.93%). MS (ES): m/z 372.17 [M+H]⁺.

Synthesis of Compound 93.1

To a solution of 93 (2.0 g, 5.39 mmol, 1.0 eq) in N,N-Dimethylformamide(30 mL), was added portionwise sodium hydride (0.258 g, 10.78 mmol, 2eq) at 0° C. and stirred for 30 min. Chloromethyl methyl ether (0.646 g,8.08 mmol, 1.5 eq) dissolved in N,N-Dimethylformamide (1 mL) was addeddropwise into the reaction mixture and stirred at 50° C. for 16 h. Aftercompletion of reaction, reaction mixture was transferred into coldwater, stirred and extracted with ethyl acetate. Organic layer wascombined, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by columnchromatography and compound was eluted in 12% ethyl acetate in hexane toobtain pure 93.1 (1.9 g, Yield: 84.93%). MS (ES): m/z 416.1 [M+H]⁺.

Synthesis of Compound 93.2

A solution of compound 93.1 (1.9 g, 4.57 mmol, 1.0 eq) intetrahydrofuran (30 mL) was cooled at −78° C. and Lithiumdiisopropylamide (2.0 mL, 13.71 mmol, 3.0 eq) was added dropwise, andstirred for 2 h at same temperature. Then iodine in tetrahydrofuran (4.6g, 18.28 mmol, 4.0 eq) was added and stirred for 2 h at sametemperature. After completion of reaction, reaction mixture wastransferred into cold water, stirred and extracted with ethyl acetate.Organic layer was combined, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by column chromatography and compound was eluted in 8% ethylacetate in hexane to obtain pure 93.2 (0.8 g, Yield: 32.31%). MS (ES):m/z 541.09 [M+H]⁺.

Synthesis of Compound 93.3

To a solution of 93.2 (0.8 g, 1.47 mmol, 1.0 eq) in 1,4-dioxane (20 mL)was added Piperidine (0.252 g, 2.94 mmol, 2.0 eq), and cesium carbonate(1.1 g, 3.67 mmol, 2.5 eq). The reaction mixture was degassed for 10min. under argon atmosphere, thentris(dibenzylideneacetone)dipalladium(0) (0.134 g, 0.14 mmol, 0.1 eq)and −4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.169 g, 0.29mmol, 0.2 eq) were added, and degassed for 5 min. The reaction wasstirred at 110° C. for 4 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 25% ethyl acetate in hexane as eluant toobtain pure 93.3 (0.127 g, Yield 17.24%). MS(ES): m/z 498.2 [M+H]⁺.

Synthesis of Compound 93.4

To a solution of compound 93.3 (0.127 g, 0.25 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.13 mL,0.75 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.62 mL, 1.25mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.37 mL, 0.75mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.4% methanol in dichloromethane to obtain 93.4(0.099 g, Yield: 78.11%), MS (ES): m/z 497.2 [M+H]⁺.

Synthesis of Compound 93.5

Compound was synthesized using general procedure B to obtain 93.5 (0.045g, Yield: 82.75%), MS (ES): m/z 273.16 [M+H]⁺.

Synthesis of compound I-96

Compound was synthesized using general procedure C to obtain I-96 (0.031g, Yield: 55.15%), MS (ES): m/z 342.50 [M+H]⁺, LCMS purity: 100%, HPLCpurity: 99.02%, ¹H NMR (DMSO-d₆, 400 MHZ): 10.88 (bs, 1H), 10.77 (s,1H), 8.14 (s, 1H), 8.04-8.03 (d, J=4.4 Hz, 1H), 6.01 (s, 1H), 3.25 (bs,4H), 2.78-2.77 (d, J=4.4 Hz, 3H), 2.16 (bs, 1H), 1.62 (bs, 6H), 0.91(bs, 1H), 0.88-0.86 (m, 3H).

Example 94:2-(2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-7-((1-methyl-11H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-97)

Synthesis of Compound 94

Compound was synthesized as per experimental protocol of core synthesisB to obtain 94 (Yield: 66.51%). MS (ES): m/z 416.1 [M+H]⁺+.

Synthesis of Compound 94.1

Compound was synthesized as per experimental protocol I-19 to obtain94.1 (Yield: 46.79%). MS (ES): m/z 302.9 [M+H]⁺.

Synthesis of Compound 94.2

Compound was synthesized using general procedure A to obtain 94.2 (0.272g, Yield: 60.89%), MS (ES): m/z 545.2 [M+H]⁺+.

Synthesis of Compound 94.3

Compound was synthesized using general procedure B to obtain 94.3 (0.170g, Yield: 93.33%), MS (ES): m/z 365.1 [M+H]⁺.

Synthesis of Compound 94.4

To a solution of compound 94.3 (0.120 g, 0.32 mmol, 1.0 eq) inDibromomethane (3 mL) was added Isoamyl nitrite (0.041 g, 0.35 mmol, 1.1eq) and Copper(II) bromide (0.035 g, 0.16 mmol, 0.5 eq) The reaction wasstirred at room temperature for 2 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain 94.4. (0.055 g, Yield: 39.01%). MS(ES): m/z 430.03[M+H]⁺.

Synthesis of Compound 94.6

To a solution of 94.4 (0.055 g, 0.12 mmol, 1.0 eq) in 1,4-dioxane (2 mL)was added 94.5 (0.023 g, 0.24 mmol, 2.0 eq), and Potassium carbonate(0.041 g, 0.3 mmol, 2.5 eq). The reaction mixture was degassed for 10min. under argon atmosphere, thentris(dibenzylideneacetone)dipalladium(0) (0.010 g, 0.012 mmol, 0.1 eq)and −4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.013 g, 0.02mmol, 0.2 eq) were added, and degassed for 5 min. The reaction wasstirred at 100° C. for 4 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 28% ethyl acetate in hexane as eluant toobtain pure 94.6. (0.037 g, Yield: 64.82%). MS(ES): m/z 446.17 [M+H]⁺.

Synthesis of Compound I-97

To a solution of compound 94.6 (0.037 g, 0.083 mmol, 1.0 eq) intetrahydrofuran (54 mL) were added N,N-Diisopropylethylamine (0.045 mL,0.24 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.2 mL, 0.41 mmol,5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.12 mL, 0.24 mmol, 3.0eq) at 0° C. Reaction mixture was stirred at 70° C. for 8 h. Aftercompletion of reaction, reaction mixture was transferred into ice coldwater and product was extracted with ethyl acetate. Organic layer wascombined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.2% methanol in dichloromethane to obtain I-97(0.019 g, Yield: 51.47%), MS (ES): m/z 445.35 [M+H]⁺, LCMS purity: 100%,HPLC purity: 99.76%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.81 (s, 1H), 9.79 (s,1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.15 (bs, 1H), 8.00 (s, 1H), 7.76-7.74(d, J=8.4 Hz, 2H), 7.59 (bs, 1H), 7.42-7.37 (m, 2H), 6.85 (s, 1H), 3.93(s, 3H), 3.79 (s, 3H), 2.81-2.80 (d, J=32 Hz, 3H).

Example 95:7-(cyclopropanecarboxamido)-2-(4-(3,3-difluoroazetidine-1-carbonyl)-2-fluorophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-98)

Synthesis of Compound 95.2

To a solution of 95 (1.0 g, 4.60 mmol, 1.0 eq), in N,N-dimethylformamide(20 mL) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (3.4 g, 9.2 mmol, 2.0 eq) and the reactionwas stirred at room temperature for 15 min. To this added was addeddiisopropylethylamine (2.54 mL, 13.8 mmol, 3.0 eq) followed by additionof 95.1 (0.593 g, 4.60 mmol, 1.0 eq). The reaction mixture was stirredat room temperature for 5 min. After completion of reaction, reactionmixture was transferred into water and product was extracted with ethylacetate. Organic layer was combined, washed with brine solution, driedover sodium sulfate and concentrated under reduced pressure to obtaincrude material. This was further purified by column chromatography andthe compound was eluted in 40% ethyl acetate in hexane to obtain 95.2(0.640 g, Yield: 47.66%). MS(ES): m/z 294.07 [M+H]⁺.

Synthesis of Compound 95.3

Compound was synthesized as per experimental protocol of core synthesisB to obtain 95.3 (Yield: 66.51%). MS (ES): m/z 416.1 [M+H]⁺.

Synthesis of Compound 95.4

Compound was synthesized using general procedure A to obtain 95.4 (0.150g, Yield: 26.64%), MS (ES): m/z 585.2 [M+H]⁺.

Synthesis of Compound 95.5

To a solution of compound 95.4 (0.150 g, 0.25 mmol, 1.0 eq) intetrahydrofuran (5 mL) were added N,N-Diisopropylethylamine (0.096 mL,0.75 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.62 mL, 1.25mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.37 mL, 0.75mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 8 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.2% methanol in dichloromethane to obtain 95.5(0.095 g, Yield: 63.44%). MS(ES): m/z 583.2 [M+H]⁺.

Synthesis of Compound 95.6

Compound was synthesized using general procedure B to obtain 95.6 (0.060g, Yield: 91.38%), MS (ES): m/z 403.13 [M+H]⁺.

Synthesis of Compound I-98

Compound was synthesized using general procedure C to obtain I-98 (0.030g, Yield: 42.78%), MS (ES): m/z 472.61 [M+H]⁺, LCMS purity: 100%, HPLCpurity: 98.25%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.20 (s, 1H), 11.37 (s, 1H),8.43 (s, 1H), 8.34 (bs, 1H), 8.11-8.08 (t, J7.6 Hz, 1H), 7.76-7.70 (m,2H), 7.58 (s, 1H), 4.91 (bs, 2H), 4.54 (bs, 2H), 2.86-2.85 (d, J=3.2 Hz,3H), 2.26 (bs, 2H), 1.06-0.96 (m, 3H).

Example 96:2-(2-fluoro-3-(2-methyloxazol-5-yl)phenyl)-N-methyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-99)

Synthesis of Compound 96

Compound was synthesized as per experimental protocol 1-81 to obtain 96(Yield: 45.58%). MS (ES): m/z 546.21 [M+H]⁺.

Synthesis of Compound 96.1

Compound was synthesized using general procedure B to obtain 96.1 (0.2g, Yield: 45.91%), MS (ES): m/z 366.11 [M+H]⁺.

Synthesis of Compound 96.2

To a solution of compound 96.1 (0.2 g, 0.54 mmol, 1.0 eq) inDibromomethane (6 mL) was added Isoamyl nitrite (0.315 g, 2.7 mmol, 5.0eq) and Copper(II) bromide (0.096 g, 0.43 mmol, 0.8 eq) The reaction wasstirred at room temperature for 2 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain 96.2 (0.047 g, Yield: 20.01%). MS(ES): m/z 430.01[M+H]⁺.

Synthesis of Compound 96.4

To a solution of 96.2 (0.047 g, 0.10 mmol, 1.0 eq) in 1,4-dioxane (2 mL)was added 96.3 (0.019 g, 0.2 mmol, 2.0 eq) and Potassium carbonate(0.034 g, 0.25 mmol, 2.5 eq). The reaction mixture was degassed for 10min. under argon atmosphere, thentris(dibenzylideneacetone)dipalladium(0) (0.010 g, 0.01 mmol, 0.1 eq)and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.012 g, 0.02 mmol,0.2 eq) were added, and degassed for 5 min. The reaction was stirred at100° C. for 4 h. After completion of reaction, reaction mixture wascooled to room temperature, transferred into water and product wasextracted with ethyl acetate. Organic layer was combined, washed withbrine solution, dried over sodium sulfate and concentrated under reducedpressure to obtain crude material. This was further purified by combiflash using 28% ethyl acetate in hexane as eluant to obtain pure 96.4.(0.026 g, Yield 53.31%). MS(ES): m/z 446.15 [M+H]⁺.

Synthesis of Compound I-99

To a solution of compound 96.4 (0.026 g, 0.058 mmol, 1.0 eq) intetrahydrofuran (5 mL) were added N,N-Diisopropylethylamine (0.032 mL,0.17 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.14 mL, 0.29mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.08 mL, 0.17mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 5 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.2% methanol in dichloromethane to obtain I-99(0.025 g, Yield: 96.37%), MS (ES): m/z 446.61 [M+H]⁺, LCMS purity: 100%,HPLC purity: 99.05%, ¹H NMR (DMSO-d₆, 400 MHZ): 12.05 (s, 1H), 10.15 (s,1H), 8.47 (s, 1H), 7.94-7.91 (t, J=7.2 Hz, 1H), 7.83-7.79 (t, J=6.8 Hz,1H), 7.64-7.63 (d, J=2 Hz, 1H), 7.59-7.58 (d, J=4 Hz, 1H), 7.55-7.51 (t,J=8 Hz, 1H), 7.42 (bs, 1H), 7.09-7.08 (d, J=6.8 Hz, 1H), 6.83 (s, 1H),3.89 (s, 3H), 3.83 (s, 3H), 2.56 (s, 3H).

Example 97:2-(3-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)-2-fluorophenyl)-N-methyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-100)

Synthesis of Compound 97

Compound was synthesized as per experimental protocol I-79 to obtain 97(Yield: 48.05%). MS (ES): m/z 588.24 [M+H]⁺.

Synthesis of Compound 97.1

Compound was synthesized using general procedure B to obtain 97.1 (0.310g, Yield: 85.99%), MS (ES): m/z 408.1 [M+H]⁺.

Synthesis of Compound 97.2

To a solution of compound 97.1 (0.310 g, 0.76 mmol, 1.0 eq) inDibromomethane (6 ml) was added Isoamyl nitrite (0.444 g, 3.8 mmol, 5.0eq) and Copper(II) bromide (0.135 g, 0.60 mmol, 0.8 eq) The reaction wasstirred at room temperature for 2 h. After completion of reaction,reaction mixture was transferred into water and product was extractedwith ethyl acetate. Organic layer was combined, washed with brinesolution, dried over sodium sulfate and concentrated under reducedpressure to obtain 97.2 (0.150 g, Yield: 41.83%). MS(ES): m/z 472.04[M+H]⁺.

Synthesis of Compound 97.4

To a solution of 97.2 (0.113 g, 0.23 mmol, 1.0 eq) in 1,4-dioxane (3 mL)was added 97.3 (0.044 g, 0.46 mmol, 2.0 eq), and Potassium carbonate(0.079 g, 0.57 mmol, 2.5 eq). The reaction mixture was degassed for 10min. under argon atmosphere, thentris(dibenzylideneacetone)dipalladium(0) (0.021 g, 0.023 mmol, 0.1 eq)and −4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.026 g, 0.046mmol, 0.2 eq) were added, and degassed for 5 min. The reaction wasstirred at 100° C. for 4 h. After completion of reaction, reactionmixture was cooled to room temperature, transferred into water andproduct was extracted with ethyl acetate. Organic layer was combined,washed with brine solution, dried over sodium sulfate and concentratedunder reduced pressure to obtain crude material. This was furtherpurified by combi flash using 28% ethyl acetate in hexane as eluant toobtain pure 97.4. (0.057 g, Yield 48.77%). MS(ES): m/z 487.1 [M+H]⁺.

Synthesis of Compound I-100

To a solution of compound 97.4 (0.057 g, 0.11 mmol, 1.0 eq) intetrahydrofuran (3 mL) were added N,N-Diisopropylethylamine (0.06 mL,0.33 mmol, 3.0 eq), Trimethylaluminium (2M in hexane, 0.27 mL, 0.55mmol, 5.0 eq) and Methylamine (2M in tetrahydrofuran, 0.16 mL, 0.33mmol, 3.0 eq) at 0° C. Reaction mixture was stirred at 70° C. for 8 h.After completion of reaction, reaction mixture was transferred into icecold water and product was extracted with ethyl acetate. Organic layerwas combined, washed with brine solution, dried over sodium sulfate andconcentrated under reduced pressure to obtain crude material. This wasfurther purified by 2.5% methanol in dichloromethane to obtain I-100(0.025 g, Yield: 43.95%), MS (ES): m/z 487.66 [M+H]⁺, LCMS purity:98.80%, HPLC purity: 95.61%, ¹H NMR (DMSO-d₆, 400 MHZ): 11.82 (s, 1H),9.78 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 78.07-8.05 (d, J=6.4 Hz, 1H),7.76-7.71 (m, 2H), 7.61 (s, 1H), 7.44-7.40 (m, 2H), 6.86 (s, 1H), 4.84(s, 2H), 3.81 (s, 3H), 2.83-2.82 (d, J=4.4 Hz, 3H), 1.36-1.34 (d, J=7.6Hz, 2H), 1.24 (bs, 2H).

Example 98. TYK2 JH2 Domain Binding Assay

Binding constants for compounds of the present invention against the JH2domain were determined by the following protocol for a KINOMEscan® assay(DiscoveRx). A fusion protein of a partial length construct of humanTYK2 (JH2domain-pseudokinase) (amino acids G556 to D888 based onreference sequence NP_003322.3) and the DNA binding domain of NFkB wasexpressed in transiently transfected HEK293 cells. From these HEK 293cells, extracts were prepared in M-PER extraction buffer (Pierce) in thepresence of Protease Inhibitor Cocktail Complete (Roche) and PhosphataseInhibitor Cocktail Set II (Merck) per manufacturers' instructions. TheTYK2(JH2domain-pseudokinase) fusion protein was labeled with a chimericdouble-stranded DNA tag containing the NFkB binding site(5′-GGGAATTCCC-3′) fused to an amplicon for qPCR readout, which wasadded directly to the expression extract (the final concentration ofDNA-tag in the binding reaction is 0.1 nM).

Streptavidin-coated magnetic beads (Dynal M280) were treated with abiotinylated small molecule ligand for 30 minutes at room temperature togenerate affinity resins for the binding assays. The liganded beads wereblocked with excess biotin and washed with blocking buffer (SeaBlock(Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand andto reduce nonspecific binding.

The binding reaction was assembled by combining 16 μl of DNA-taggedkinase extract, 3.8 μl liganded affinity beads, and 0.18 μl testcompound (PBS/0.05% Tween 20/10 mM DTT/0.1% BSA/2 μg/ml sonicated salmonsperm DNA). Extracts were used directly in binding assays without anyenzyme purification steps at a ≥10,000-fold overall stock dilution(final DNA-tagged enzyme concentration <0.1 nM). Extracts were loadedwith DNA-tag and diluted into the binding reaction in a two stepprocess. First extracts were diluted 1:100 in 1× binding buffer(PBS/0.05% Tween 20/10 mM DTT/0.1% BSA/2 μg/ml sonicated salmon spermDNA) containing 10 nM DNA-tag. This dilution was allowed to equilibrateat room temperature for 15 minutes and then subsequently diluted 1:100in 1× binding buffer. All reactions were performed in polypropylene384-well plates. Each was a final volume of 0.02 mL. Assays wereincubated with shaking for 1 hour at room temperature. Then the beadswere pelleted and washed with wash buffer (1×PBS, 0.05% Tween 20) toremove displaced kinase and test compound. The washed based werere-suspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μMnon-biotinylated affinity ligand) and incubated at room temperature withshaking for 30 minutes. The kinase concentration in the eluates wasmeasured by qPCR. qPCR reactions were assembled by adding 2.5 μL ofkinase eluate to 7.5 μL of qPCR master mix containing 0.15 μM ampliconprimers and 0.15 μM amplicon probe. The qPCR protocol consisted of a 10minute hot start at 95° C., followed by 35 cycles of 95° C. for 15seconds, 60° C. for 1 minute.

Test compounds were prepared as 111× stocks in 100% DMSO. K_(d) valueswere determined using an 11-point 3-fold compound dilution series withthree DMSO control points. All compounds for K_(d) measurements aredistributed by acoustic transfer (non-contact dispensing) in 100% DMSO.The compounds were then diluted directly into the assays such that thefinal concentration of DMSO was 0.9%. The K_(d) values were determinedusing a compound top concentration of 30,000 nM. K_(d) measurements wereperformed in duplicate.

Binding constants (K_(d)s) were calculated with a standard dose-responsecurve using the Hill equation:

${Response} = {{Background} + \frac{\left( {{Signal} - {Background}} \right)}{\left( {1 + \left( \frac{{Kd}^{{Hill}\mspace{14mu}{Slope}}}{{Dose}^{{Hill}\mspace{14mu}{Slope}}} \right)} \right.}}$

The Hill Slope was set to −1. Curves were fitted using a non-linearleast square fit with the Levenberg-Marquardt algorithm (Levenberg, K.,A method for the solution of certain non-linear problems in leastsquares, Q. Appl. Math. 2, 164-168 (1944)).

Results of the TYK2 JH2 Domain Binding Assay are presented in Table 2.Compounds denoted as “A” had a Kd lower than 200 μM; compounds denotedas “B” had a Kd between 200 μM and 1 nM; compounds denoted as “C” had aKd between 1 nM and 10 nM; and compounds denoted as “D” had a Kd greaterthan 10 nM.

TABLE 2 Results of Tyk2 JH2 Domain Binding Assay Compound Tyk2 JH2 KdI-1 C I-2 A I-3 B I-4 A I-5 C I-6 A I-7 B I-8 C I-9 B I-10 B I-11 B I-12A I-13 A I-14 B I-15 B I-16 A I-17 B I-18 B I-19 A I-20 B I-21 A I-22 AI-23 A I-24 A I-25 A I-26 A I-27 A I-28 B I-29 B I-30 A I-31 C I-32 BI-33 B I-34 A I-35 B I-36 A I-37 C I-38 C I-39 C I-40 C I-41 C I-42 AI-43 B I-44 A I-45 B I-46 B I-47 A I-48 A I-49 A I-50 B I-51 B I-52 AI-53 B I-54 A I-55 B I-56 B I-57 C I-58 A I-59 B I-60 A I-61 D I-62 AI-63 B I-64 D I-65 A I-66 A I-67 A I-68 A I-69 A I-70 B I-71 D I-72 DI-73 A I-74 A I-75 A I-76 A I-77 A I-78 A I-79 A I-80 A I-81 A I-82 DI-83 A I-84 A I-85 B I-86 A I-87 A I-88 A I-89 B I-90 A I-91 A I-92 AI-93 B I-94 A I-95 A I-96 D I-97 A I-98 A I-99 A I-100 A I-101 B

Example 99. TYK2 & JAK2 Radioactive Kinase Assay

Peptide substrate, [KKSRGDYMTMQIG], (20 μM) was prepared in reactionbuffer (20 mM Hepes pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35, 0.02mg/mL BSA, 0.1 mM Na₃PO₄, 2 mM DTT, 1% DMSO). TYK2 (Invitrogen) kinasewas added, followed by compounds in DMSO. ³³PATP was added to initiatethe reaction in ATP at 10 μM. The kinase reaction was incubated for 120min at room temp and reactions were spotted onto P81 ion exchange paper(Whatman #3698-915), and then washed extensively in 0.75% phosphoricacid, prior to reading the radioactivity counts. For JAK2 (Invitrogen)kinase assay the peptide substrate poly[Glu:Tyr](4:1), 0.2 mg/ml wasused, in the reaction carried out the same as for TYK2.

The TYK2 and JAK2 radioactive kinase assay measures the percentinhibition at the TYK2 kinase domain (JH1) and the percent inhibition atthe JAK2 kinase domain (JH1). Results of the assay are expressed aspercent inhibition at 10 μM.

Results of the TYK2 and JAK2 Radioactive Kinase Assay are presented inTable 3. Compounds denoted as “A” had a percent inhibition at 10 μMlower than 50; compounds denoted as “B” had a percent inhibition at 10μM between 50 and 70; compounds denoted as “C” had a percent inhibitionat 10 μM between 70 and 90; and compounds denoted as “D” had a percentinhibition at 10 μM greater than 90.

TABLE 3 TYK2 & JAK2 Radioactive Kinase Assay TYK2 JH1 JAK2 JH1 %Inhibition % Inhibition Compound @ 10 μM @ 10 μM I-1 A A I-2 A A I-3 A AI-4 A A I-5 A A I-6 A A I-7 A A I-8 A A I-9 A A I-10 A A I-11 A A I-12 DD I-13 A A I-14 A A I-15 A A I-16 A A I-17 A A I-18 A A I-19 A A I-20 AA I-21 A A I-22 A A I-23 A A I-24 A A I-25 A A I-26 A A I-27 A A I-28 AA I-29 A A I-30 A A I-31 A A I-32 A A I-33 A A I-34 A A I-35 A A I-36 AA I-37 A A I-38 A A I-39 A A I-40 A A

Example 100. TYK2 & JAK2 Caliper Assay

The caliper machine employs an off chip mobility shift assay to detectphosphorylated peptide substrates from kinase assays, usingmicrofluidics technology. The assays were carried out at ATPconcentration equivalent to the ATP Km, and at 1 mM ATP. Compounds wereserially diluted in DMSO then further diluted in assay buffer (25 mMHEPES, pH 7.5, 0.01% Brij-35, 0.01% Triton, 0.5 mM EGTA). 5 ul ofdiluted compound was added into wells first, then 10 ul of enzyme mixwas added into wells, followed by 10 uL of substrate mix (peptide andATP in 10 mM MgCl₂) to start reaction. Reaction was incubated at 28° C.for 25 min and then added 25 ul stop buffer (100 mM HEPES, 0.015%Brij-35, 50 mM EDTA), followed by reading with Caliper. JAK2 at 1 nMfinal concentration and TYK2 at 9.75 nM are from Carna, and substratesused are ATP at 20 and 16 uM, respectively. JAK2 assay uses peptide 22and TYK2 uses peptide 30 (Caliper), each at 3 uM.

Example 101. IL-12 Induced pSTAT4 in Human PBMC

Human PBMC were isolated from buffy coat and were stored frozen forassays as needed. Cells for assay were thawed and resuspended incomplete media containing serum, then cells were diluted to 1.67 E6cells/mL so that 120 μl per well is 200,000 cells. 15 μl of compound orDMSO was added to the well at the desired concentrations and incubatedat 1 hr at 37 C. 15 μl of stimulus (final concentration of 1.7 ng/mLTL-12) was added for 30 minutes prior to pSTAT4 and total STAT4 analysisusing cell lysates prepared and analyzed by MSD reagents as permanufacturer protocol. The final DMSO concentration of compound in theassay was 0.1%.

The IL-12 Induced pSTAT4 assay evaluates the inhibition of IL-12 inducedSTAT4 phophorylation mediated by TYK2/JAK2 (heterodimeric complex).

Results of the IL-12 Induced pSTAT4 in human PBMC are presented in Table4. Compounds denoted as “A” had an IC₅₀ lower than 0.1 μM; compoundsdenoted as “B” had an IC₅₀ between 0.1 and 0.5 μM; compounds denoted as“C” had an IC₅₀ between 0.5 and 1.0 μM; and compounds denoted as “D” hadan IC₅₀ greater than 1.0 μM.

TABLE 4 IL-12 Induced pSTAT4 in human PBMC assay results. CompoundIL-12-pSTAT4 IC₅₀ (μM) I-1 C I-2 A I-4 A I-12 A I-19 A I-23 A I-24 AI-42 A I-48 A I-52 A I-54 B

Example 102. GM-CSF Induced pSTAT5 in Human PBMC

Cells were prepared for analysis as in the above procedure and 15 μl ofGM-CSF (final concentration 5 ng/mL) was added for 20 minutes prior topSTAT5 and total STAT5 analysis using cell lysates prepared and analyzedby MSD reagents as per manufacturer protocol. The final DMSOconcentration of compound in the assay was 0.1%.

The GM-CSF Induced pSTAT5 assay is a JAK2 cellular selectivity assaywhich evaluates inhibition of GM-CSF induced STAT5 phopsphorylationmediated by the JAK2/JAK2 homodimeric complex.

Results of the GM-CSF Induced pSTAT5 assay are presented in Table 5.Compounds denoted as “A” had an IC₅₀>50 μM; compounds denoted as “B” hadan IC₅₀ result of >12.5, >20, >25, or >30 μM; compounds denoted as “C”had an IC₅₀ result of >2.5 or >10 μM; and compounds denoted as “D” hadan IC₅₀ result of >0.3, >0.5, or >1.0 μM.

TABLE 5 GM-CSF Induced pSTAT5 assay results. Compound PBMC_GMCSF_pSTAT5IC₅₀ (μM) I-1 A I-2 A I-4 B I-12 D I-19 D I-23 A

Example 103. Ex Vivo Mouse IL-12 Induced IFNγ Studies

C57/BL6 mice are given a single oral dose of either vehicle or differentdoses of compound at a volume of 10 mL/kg. 30 minutes to 1 hour afterdosing, animals are euthanized and blood was collected via vena cavainto sodium heparin blood collection tubes and inverted several times.Blood is then plated on anti-CD3 coated plates and stimulated with 2ng/ml of mouse IL-12 in RPMI media for 24 hours at 37° C. in humidifiedincubator with 5% CO₂. At the end of the incubation, blood iscentrifuged at 260 g for 5 minutes to collect supernatant. IFNγconcentration in the supernatant is determined with mouse IFNγ MSD kitper manufacture's instruction (Meso Scale Discovery). At the time of theblood collection, plasma is collected for drug level analysis byLC-MS/MS.

Example 104. T-ALL Cell Proliferation Assay

T-ALL cell lines KOPT-K1, HPB-ALL, DND-41, PEER, and CCRF-CEM arecultured in RPMI-1640 medium with 10% fetal bovine serum andpenicillin/streptomycin. Cells are plated in triplicate at 1×10⁴ cellsper well in 96-well plates. T-ALL cell lines DU.528, LOUCY, and SUP-T13are cultured in the same medium and plated at a density of 1.5×10⁴ cellsper well. The cells are treated with DMSO or different concentrations ofeach compound of the invention. Cell viability at 72 hour exposure tothe drug is assessed by CellTiter-Glo Luminescent Cell Viability Assay(Promega). CellTiter-Glo Reagent is added into the well and incubatedfor 10 minutes. Luminescence is measured subsequently using a 96-wellplate luminescence reader. Cell viability is calculated by using theDMSO treated samples as 100%. IC₅₀ value is calculated by nonlinearregression using GraphPad Prism software.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A method of treating a TYK2-mediated disorder, disease, orcondition in a patient comprising administering to said patient thecompound of formula I′:

or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; L¹is a covalent bond or a C₁₋₄ bivalent saturated or unsaturated, straightor branched hydrocarbon chain wherein one or two methylene units of thechain are optionally and independently replaced by —C(R⁴)₂—, —N(R)—,—N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—,—C(O)O—, —S—, —S(O)— or —S(O)₂—; R⁴ is independently R^(A) or R^(B);each instance of R^(A) is independently halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)(NR)R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R, or —P(O)R₂; ortwo instances of R^(A) are optionally taken together to form an oxo;each instance of R^(B) is independently C₁₋₆ aliphatic; phenyl; a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring; a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora 7-12 membered saturated or partially unsaturated bicyclic heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each of which is substituted by q instances ofR^(C); each instance of R^(C) is independently oxo, halogen, —CN, —NO₂,—OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —S(O)NR₂, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,—N(R)C(O)NR₂, —N(R)C(NR)NR₂, —N(R)NR₂, —N(R)S(O)₂NR₂, —N(R)S(O)₂R,—N═S(O)R₂, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(R)NR₂, —P(O)(R)OR or—P(O)R₂ or an optionally substituted group selected from C₁₋₆ aliphatic;phenyl; naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur; a 5-8 membered saturated or partially unsaturated bridgedbicyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 6-10 membered saturated or partiallyunsaturated spirocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated orpartially unsaturated bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 3-7 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen,phosphorous, silicon and sulfur; and a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; or for each instance of R^(B), optionally:two R^(C) groups on the same atom are taken together with the atom toform an optionally substituted 4-7 membered saturated, spirocyclicheterocyclic ring having 1-2 heteroatoms, independently selected fromnitrogen, oxygen, and sulfur; two R^(C) groups are taken together withtheir intervening atoms to form an optionally substituted 4-7 memberedsaturated or partially unsaturated, fused ring having 0-2 heteroatoms,independently selected from nitrogen, oxygen, and sulfur; or two R^(C)groups are taken together with their intervening atoms to form anoptionally substituted 5-6 membered fused aryl ring having 0-3heteroatoms, independently selected from nitrogen, oxygen, and sulfur;each R is independently hydrogen, or an optionally substituted groupselected from C₁₋₆ aliphatic; phenyl; naphthalenyl; an 8-10 memberedbicyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; a 7-12membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur;or: two R groups on the same nitrogen are taken together with thenitrogen to form an optionally substituted 4-7 membered monocyclicsaturated, partially unsaturated, or heteroaryl ring having, in additionto the nitrogen, 0-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur; R¹ is Cy¹; Cy¹ is phenyl; a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; a 3-7 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring; or a 7-12 membered saturated orpartially unsaturated bicyclic heterocyclic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein Cy¹ issubstituted with p instances of R^(1A); each instance of R^(1A), isindependently R^(A) or R^(B); R² is C₁₋₆ aliphatic; phenyl; a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring; a 3-7 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora 7-12 membered saturated or partially unsaturated bicyclic heterocyclicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each of which is substituted by q instances ofR^(C); R³ is —C(O)NH₂, —C(O)NHCH₃, or —C(O)NHCD₃; each of p and q isindependently 0, 1, 2, 3, or 4; and r is 0 or 1; wherein theTYK2-mediated disorder, disease, or condition is: an autoimmune disorderselected from type 1 diabetes, ankylosing spondylitis, cutaneous lupuserythematosus, systemic lupus erythematosus, multiple sclerosis,systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, andinflammatory bowel disease; an inflammatory disorder selected fromrheumatoid arthritis, asthma, chronic obstructive pulmonary disease,psoriasis, Crohn's disease, ulcerative colitis, and inflammatory boweldisease; a hematological cancer: or Alzheimer's disease.
 2. The methodof claim 1 wherein the autoimmune disorder is selected from type 1diabetes, ankylosing spondylitis, cutaneous lupus erythematosus,systemic lupus erythematosus, multiple sclerosis, systemic sclerosis,psoriasis, Crohn's disease, ulcerative colitis, and inflammatory boweldisease.
 3. The method of claim 1 wherein the inflammatory disorder isselected from rheumatoid arthritis, asthma, chronic obstructivepulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, andinflammatory bowel disease.
 4. The method of claim 1 wherein theproliferative disorder is a hematological cancer.
 5. The method of claim1 wherein the hematological cancer is a leukemia.
 6. The method of claim5 wherein the leukemia is a T-cell leukemia.
 7. The method of claim 6wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia(T-ALL).
 8. The method of claim 1 wherein the TYK2-mediated disorder,disease, or condition is type 1 diabetes.
 9. The method of claim 1wherein the TYK2-mediated disorder, disease, or condition is ankylosingspondylitis.
 10. The method of claim 1 wherein the TYK2-mediateddisorder, disease, or condition is cutaneous lupus erythematosus. 11.The method of claim 1 wherein the TYK2-mediated disorder, disease, orcondition is systemic lupus erythematosus.
 12. The method of claim 1wherein the TYK2-mediated disorder, disease, or condition is multiplesclerosis.
 13. The method of claim 1 wherein the TYK2-mediated disorder,disease, or condition is systemic sclerosis.
 14. The method of claim 1wherein the TYK2-mediated disorder, disease, or condition is psoriasis.15. The method of claim 1 wherein the TYK2-mediated disorder, disease,or condition is Crohn's disease.
 16. The method of claim 1 wherein theTYK2-mediated disorder, disease, or condition is ulcerative colitis. 17.The method of claim 1 wherein the TYK2-mediated disorder, disease, orcondition is inflammatory bowel disease.
 18. The method of claim 1wherein the TYK2-mediated disorder, disease, or condition is rheumatoidarthritis.
 19. The method of claim 1 wherein the TYK2-mediated disorder,disease, or condition is asthma.
 20. The method of claim 1 wherein theTYK2-mediated disorder, disease, or condition is chronic obstructivepulmonary disease.